Anticancer actions of carnosine in cellular models of prostate cancer.

Treatments for organ-confined prostate cancer include external beam radiation therapy, radical prostatectomy, radiotherapy/brachytherapy, cryoablation and high-intensity focused ultrasound. None of these are cancer-specific and are commonly accompanied by side effects, including urinary incontinence and erectile dysfunction. Moreover, subsequent surgical treatments following biochemical recurrence after these interventions are either limited or affected by the scarring present in the surrounding tissue. Carnosine (ß-alanyl-L-histidine) is a histidine-containing naturally occurring dipeptide which has been shown to have an anti-tumorigenic role without any detrimental effect on healthy cells; however, its effect on prostate cancer cells has never been investigated. In this study, we investigated the effect of carnosine on cell proliferation and metabolism in both a primary cultured androgen-resistant human prostate cancer cell line, PC346Flu1 and murine TRAMP-C1 cells. Our results show that carnosine has a significant dose-dependent inhibitory effect in vitro on the proliferation of both human (PC346Flu1) and murine (TRAMP-C1) prostate cancer cells, which was confirmed in 3D-models of the same cells. Carnosine was also shown to decrease adenosine triphosphate content and reactive species which might have been caused in part by the increase in SIRT3 also shown after carnosine treatment. These encouraging results support the need for further human in vivo work to determine the potential use of carnosine, either alone or, most likely, as an adjunct therapy to surgical or other conventional treatments.

Current data processing methods and reporting standards for untargeted analysis of volatile organic compounds using direct mass spectrometry: a systematic review.

INTRODUCTION: Untargeted direct mass spectrometric analysis of volatile organic compounds has many potential applications across fields such as healthcare and food safety. However, robust data processing protocols must be employed to ensure that research is replicable and practical applications can be realised. User-friendly data processing and statistical tools are becoming increasingly available; however, the use of these tools have neither been analysed, nor are they necessarily suited for every data type. OBJECTIVES: This review aims to analyse data processing and analytic workflows currently in use and examine whether methodological reporting is sufficient to enable replication. METHODS: Studies identified from Web of Science and Scopus databases were systematically examined against the inclusion criteria. The experimental, data processing, and data analysis workflows were reviewed for the relevant studies. RESULTS: From 459 studies identified from the databases, a total of 110 met the inclusion criteria. Very few papers provided enough detail to allow all aspects of the methodology to be replicated accurately, with only three meeting previous guidelines for reporting experimental methods. A wide range of data processing methods were used, with only eight papers (7.3%) employing a largely similar workflow where direct comparability was achievable. CONCLUSIONS: Standardised workflows and reporting systems need to be developed to ensure research in this area is replicable, comparable, and held to a high standard. Thus, allowing the wide-ranging potential applications to be realised.

Ambient air pollution, covert cerebrovascular disease and cognition: results from the ISSYS study.

BACKGROUND AND PURPOSE: Although air pollution (AP) has been associated with stroke and dementia, data regarding its relationship with covert cerebrovascular disease (cCVD) and cognition over time are sparse. The aim of this study was to explore these relationships. METHODS: A prospective population-based study of 976 stroke-free and non-demented individuals living in Barcelona, Spain, was conducted during 2010-2016. A land use regression model was used to estimate the exposure of each participant to AP: NOx, NO2, PM2.5, PM10, PMcoarse and PM2.5 absorbance. Cognitive function and cCVD were assessed at baseline (n = 976) and 4 years after (n = 317). Multivariate-adjusted models were developed. RESULTS: At baseline, 99 participants (10.1%) had covert brain infarcts and 91 (9.3%) had extensive periventricular white matter hyperintensities (WMHs). Marked subcortical WMH progression was seen in 19.7%; the incidence of other covert cerebrovascular lessons ranged between 5% and 6% each. PM2.5 was related to higher odds of having a covert brain infarct (odds ratio [OR] 2.21; 95% confidence interval [CI] 1.06-4.60). PM2.5 absorbance was related to higher odds of having extensive subcortical WMHs (OR 1.72; 95% CI 1.13-2.60), whereas NO2 was related to higher odds of having extensive subcortical (OR 1.66; 95% CI 1.17-2.35) or periventricular (OR 1.96; 95% CI 1.10-3.50) WMHs and to higher odds of developing marked subcortical WMH progression (OR 1.40; 95% CI 1.05-1.90). NOx was related to incident cerebral microbleeds (OR 1.36; 95% CI 1.04-1.79). There was no association between AP and cognition. CONCLUSIONS: Air pollutant predicts the presence and accumulation of cCVD. Its impact on cognitive impairment remains to be determined.

Barriers and facilitators associated with the implementation of surgical safety checklists: A qualitative systematic review.

AIM: Despite the documented benefits of the World Health Organisation Patient Safety Checklist compliance rates with implementation continue to cause risk to patient safety. This qualitative systematic review aimed to explore the reported factors that impact compliance and implementation processes related to surgical safety checklists in perioperative settings. DESIGN: A qualitative systematic review. METHODS: A systematic review using the Joanna Briggs Institute (JBI) approach to synthesize qualitative studies was conducted and reported according to PRISMA guidelines. Electronic databases were expansively searched using keywords and subject headings. Articles were assessed using a pre-selected eligibility criterion. Data extraction and quality appraisal was undertaken for all included studies and a meta-aggregation performed. DATA SOURCES: The CINAHL, Medline and Scopus databases were searched in August 2022 and the search was repeated in June 2023. RESULTS: 34 studies were included. Following the synthesis of the findings there were multiple interrelating barriers to checklist compliance that impacted implementation. There were more barriers than enablers reported in existing studies. Enablers included effective leadership, education and training, timely use of audit and feedback, local champions, and the option for local modifications to the surgical checklist. Further research should focus on targeted interventions that improve observed compliance rates to optimize patient safety. CONCLUSION: This qualitative systematic review identified multiple key factors that influenced the uptake of the Surgical Safety Checklist in operating theatres. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Surgeon participation, hierarchical culture, complacency, and duplication of existing safety processes were identified which impacted the use and completion of the checklist.

Sequence-Specific Fluorescence Turn-On Sensing of RNA by DNA Probes Incorporating the Tricyclic Cytidine Analogue DEAtC.

Sequence-specific fluorescent probes for RNA are widely used in microscopy applications such as fluorescence in situ hybridization and a growing number of newer approaches to live-cell RNA imaging. The sequence specificity of most of these approaches relies on differential hybridization of the probe to the correct target. Competing sequences with only one or two base mismatches are prone to causing off-target recognition. Here, we report the sequence-specific fluorescent detection of model RNA targets using a tricyclic cytidine analogue DEAtC that is included as a surrogate for natural cytidine in DNA probe strands and that reports directly on Watson-Crick base pairing. The DEAtC-containing DNA oligonucleotide probes exhibit an average 8-fold increase in fluorescence intensity when hybridized to matched RNA with DEAtC base paired with G and little fluorescence turn-on when DEAtC is base paired with A. Duplex structure determination by NMR, time-resolved fluorescence studies, and Stern-Volmer quenching experiments suggest that the combination of greater π stacking and narrower grooves in the A-form DNA-RNA heteroduplex provides additional shielding and favorable electronic interactions between bases, explaining why DEAtC's fluorescence turn-on response to RNA targets is typically 3-fold greater than for DNA targets.

Preoperative, technical, and postoperative considerations for skull base reconstruction: a practical review of critical concepts.

Despite widespread adoption and advances in endoscopic skull base surgery, with expanding indications and the ability to effectively treat larger and more complex pathologies, skull base reconstruction following tumor resection and prevention of cerebrospinal fluid leak remains a challenge for even the most seasoned of surgical teams. Mounting evidence in all areas have pushed our understanding of skull base reconstruction principles forward. In this narrative review, we summarize critical concepts and provide practical but comprehensive guiding principles on preoperative, intraoperative/technical, and postoperative management principles related to optimizing skull base reconstructive success. The goal is to provide an informative resource for skull base surgeons (both otolaryngologists and neurosurgeons) to reference regarding state-of-the-art evidence surrounding this ever-evolving topic.

Bayesian emulation and history matching of JUNE.

We analyze JUNE: a detailed model of COVID-19 transmission with high spatial and demographic resolution, developed as part of the RAMP initiative. JUNE requires substantial computational resources to evaluate, making model calibration and general uncertainty analysis extremely challenging. We describe and employ the uncertainty quantification approaches of Bayes linear emulation and history matching to mimic JUNE and to perform a global parameter search, hence identifying regions of parameter space that produce acceptable matches to observed data, and demonstrating the capability of such methods. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Prevalence and commonality of non-technical skills and human factors in airway management guidelines: a narrative review of the last 5 years.

The primary aim of this review was to identify, analyse and codify the prominence and nature of human factors and ergonomics within difficult airway management algorithms. A directed search across OVID Medline and PubMed databases was performed. All articles were screened for relevance to the research aims and according to predetermined exclusion criteria. We identified 26 published airway management algorithms. A coding framework was iteratively developed identifying human factors and ergonomic specific words and phrases based on the Systems Engineering Initiative for Patient Safety model. This framework was applied to the papers to delineate qualitative and quantitative results. Our results show that human factors are well represented within recent airway management guidelines. Human factors associated with work systems and processes featured more prominently than user and patient outcome measurement and adaption. Human factors are an evolving area in airway management and our results highlight that further considerations are necessary in further guideline development.

"I must do this!": A latent profile analysis approach to understanding the role of irrational beliefs and motivation regulation in mental and physical health.

In the research concerning rational emotive behaviour therapy (REBT) in sport and exercise, irrational beliefs are proposed as a risk factor for health. Concurrent to this, researchers have also indicated that autonomous and controlled motivation, as proposed in organismic integration theory could, together with irrational beliefs, determine individual health. However, research is yet to align irrational beliefs and motivation, and explore how this alignment relates to mental health. The present two study paper identifies individual subgroups, drawn from data concerning irrational beliefs, motivation, and health (psychological distress, and physical health), in a sample of exercisers (study 1) and student athletes (study 2). We examined the latent profile structure of irrational beliefs and motivation, and how these latent profiles relate to psychological distress (studies 1 and 2), and physical health (study 2). Results indicate a two class profile whereby class 1 is characterised by high irrational beliefs, low self-determined motivation, and poor health outcomes. Class 2 is characterised by low irrational beliefs, high self-determined motivation, and better health outcomes. The findings are discussed in relation to the theoretical implications for REBT and organismic integration theory, and the practical implications for key stakeholders in the health of exercise participants and athletes.

Implementing Medical Student Teaching on Gynaecological Healthcare of Transgender Patients.

Introduction Transgender people have specific healthcare needs and experience difficulty in accessing health services. Medical students should receive teaching on general and gynaecological healthcare issues in this population. Our aim was to assess medical students' knowledge of healthcare needs of transgender people before and after a newly implemented teaching session on transgender healthcare. Method A mixed-method study was carried out over a three month period in a university obstetric and gynaecology hospital in Dublin. A one-hour teaching session was developed and delivered to final year medical students. Students completed a survey before and after receiving the lecture. Results Seventy-one students completed the pre-lecture survey and forty-three completed the post-lecture survey. Pre-lecture, 64 students (90%) reported some-to-no understanding of healthcare issues of transgender people, and only 13 (18%) reported understanding gynaecological issues faced by transgender people. Post-lecture, 41 (95%) had a better understanding of health issues faced by this population and 40 (93%) had a better understanding of gynaecological health issues faced. Most students (81%) wanted further teaching on the topic. Conclusion A one-hour teaching session was effective at improving student knowledge of care of transgender people. This teaching could be expanded to all Irish medical schools. Going forward, the teaching could be adapted for post-graduate obstetric and gynaecology teaching.

Air Pollution Levels Outside the Capital's Maternity Hospitals.

Introduction The World Health Organisation has identified air pollution as the single biggest environmental threat to human health. There is growing evidence in the literature that air pollution is associated with negative outcomes in pregnancy. The purpose of this study was to measure pollution levels in the immediate surroundings of the three Dublin maternity hospitals by measuring fine particulate matter <2.5 micrometres (PM2.5). Methods Data pertaining to levels of PM2.5 at the three Dublin maternity hospitals were obtained from Pollutrack's records for the time period 25/6/2021-2/12/2021. Results were compared to the 2021 WHO Air Quality Guidelines. Results Average PM2.5 levels were 9µg/m³ around the National Maternity Hospital, 10µg/m³ around the Coombe Hospital and 13µg/m³ around the Rotunda Hospital. Levels were higher during the day, weekdays and in December. No matter when the PM2.5 levels were measured, results were higher than those recommended by the World Health Organisation's Air Quality Guideline. Discussion Air pollution levels across Ireland's capital city are higher than recommended by the WHO. This is concerning for the public and in particular for the pregnant population. Going forward, further research is required on the relationship between levels of air pollutants and adverse pregnancy outcomes in Dublin.

Core Imaging Library - Part I: a versatile Python framework for tomographic imaging.

We present the Core Imaging Library (CIL), an open-source Python framework for tomographic imaging with particular emphasis on reconstruction of challenging datasets. Conventional filtered back-projection reconstruction tends to be insufficient for highly noisy, incomplete, non-standard or multi-channel data arising for example in dynamic, spectral and in situ tomography. CIL provides an extensive modular optimization framework for prototyping reconstruction methods including sparsity and total variation regularization, as well as tools for loading, preprocessing and visualizing tomographic data. The capabilities of CIL are demonstrated on a synchrotron example dataset and three challenging cases spanning golden-ratio neutron tomography, cone-beam X-ray laminography and positron emission tomography. This article is part of the theme issue 'Synergistic tomographic image reconstruction: part 2'.

The design and use of a simple device for the MRI assessment of changes in cardiovascular function by lower-body negative-pressure-simulated reduction of central blood volume.

AIM: To use a locally designed and simple lower-body negative-pressure (LBNP) device and 1.5 T magnetic resonance imaging (MRI) to demonstrate the ability to assess changes in cardiovascular function during preload reduction. These effects were evaluated on ventricular volumes and great vessel flow in healthy volunteers, for which there are limited published data. MATERIAL AND METHODS: After ethical review, 14 volunteers (mean age 33.9 ± 7 years, mean body mass index [BMI] 23.1 ± 2.5) underwent LBNP prospectively at 0, -5, -10, and -20 mmHg pressure, using a locally designed LBNP box. Expiratory breath-hold biventricular volumes, and free-breathing flow imaging of the ascending aorta and main pulmonary artery were acquired at each level of LBNP. RESULTS: At -5 mmHg, there was no change in aortic flow or left ventricular volumes versus baseline. Right ventricular output (p=0.013) and pulmonary net flow (p=0.026) decreased. At -20 mmHg, aortic and pulmonary net flow (p<0.001) decreased, as were left and right ventricular end diastolic volume (p<0.001) and left and right end systolic volumes (p=0.038 and p=0.003 respectively). CONCLUSIONS: Use of a MRI-compatible LBNP device is feasible to measure changes in ventricular volume and great arterial flow in the same experiment. This may enhance further research into the effects of preload reduction by MRI in a wide range of important cardiovascular pathologies.

Adult Plant Leaf Rust Resistance in AC Taber Wheat Maps to Chromosomes 2BS and 3BS.

AC Taber is a hard red spring wheat cultivar that has had long-lasting resistance to the leaf rust fungus Puccinia triticina. The objective of this study was to determine the chromosome location of the leaf rust resistance genes in AC Taber. The leaf rust-susceptible cultivar Thatcher was crossed with AC Taber to develop an F6 recombinant inbred line (RIL) population. The RILs and parents were evaluated for segregation of leaf rust resistance in five field plot tests and in two seedling tests to race BBBDB of P. triticina. A genetic map of the RIL population was developed using 90,000 single nucleotide polymorphism markers with the Illumina Infinium iSelect 90K wheat bead array. Quantitative trait loci (QTLs) with significant effects for lower leaf rust severity in the field plot tests were found on chromosomes 2BS and 3BS. The same QTLs also had significant effects for lower infection type in seedlings to leaf rust race BBBDB. The gene on 2BS was the adult plant resistance gene Lr13, and the gene on 3BS mapped to the same region as the adult plant resistance gene Lr74 and other QTLs for leaf rust resistance. Kompetitive allele-specific PCR assay markers linked to the 2BS and 3BS regions were developed and should be useful for marker-based selection of these genes.

A 7-day high-fat, high-calorie diet induces fibre-specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle.

KEY POINTS: We have recently shown that a high-fat, high-calorie (HFHC) diet decreases whole body glucose clearance without impairing skeletal muscle insulin signalling, in healthy lean individuals. These diets are also known to increase skeletal muscle IMTG stores, but the effect on lipid metabolites leading to skeletal muscle insulin resistance has not been investigated. This study measured the effect of 7 days' HFHC diet on (1) skeletal muscle concentration of lipid metabolites, and (2) potential changes in the perilipin (PLIN) content of the lipid droplets storing intramuscular triglyceride (IMTG). The HFHC diet increased PLIN3 protein expression and redistributed PLIN2 to lipid droplet stores in type I fibres. The HFHC diet increased IMTG content in type I fibres, while lipid metabolite concentrations remained the same. The data suggest that the increases in IMTG stores assists in reducing the accumulation of lipid metabolites known to contribute to skeletal muscle insulin resistance. ABSTRACT: A high-fat, high-calorie (HFHC) diet reduces whole body glucose clearance without impairing skeletal muscle insulin signalling in healthy lean individuals. HFHC diets also increase skeletal muscle lipid stores. However, unlike certain lipid metabolites, intramuscular triglyceride (IMTG) stored within lipid droplets (LDs) does not directly contribute to skeletal muscle insulin resistance. Increased expression of perilipin (PLIN) proteins and colocalisation to LDs has been shown to assist in IMTG storage. We aimed to test the hypothesis that 7 days on a HFHC diet increases IMTG content while minimising accumulation of lipid metabolites known to disrupt skeletal muscle insulin signalling in sedentary and obese individuals. We also aimed to identify changes in expression and subcellular distribution of proteins involved in IMTG storage. Muscle biopsies were obtained from the m. vastus lateralis of 13 (11 males, 2 females) healthy lean individuals (age: 23 ± 2.5 years; body mass index: 24.5 ± 2.4 kg m-2 ), following an overnight fast, before and after consuming a high-fat (64% energy), high-calorie (+47% kcal) diet for 7 days. After the HFHC diet, IMTG content increased in type I fibres only (+101%; P < 0.001), whereas there was no change in the concentration of either total diacylglycerol (P = 0.123) or total ceramides (P = 0.150). Of the PLINs investigated, only PLIN3 content increased (+50%; P < 0.01) solely in type I fibres. LDs labelled with PLIN2 increased (+80%; P < 0.01), also in type I fibres only. We propose that these adaptations of LDs support IMTG storage and minimise accumulation of lipid metabolites to protect skeletal muscle insulin signalling following 7 days' HFHC diet.

Effect of sildenafil on maternal hemodynamics in pregnancies complicated by severe early-onset fetal growth restriction: planned subgroup analysis from a multicenter randomized placebo-controlled double-blind trial.

OBJECTIVES: Fetal growth restriction (FGR) is associated with maternal cardiovascular changes. Sildenafil, a phosphodiesterase type-5 inhibitor, potentiates the actions of nitric oxide, and it has been suggested that it alters maternal hemodynamics, potentially improving placental perfusion. Recently, the Dutch STRIDER trial was stopped prematurely owing to excess neonatal mortality secondary to pulmonary hypertension. The main aim of this study was to investigate the effect of sildenafil on maternal hemodynamics in pregnancies with severe early-onset FGR. METHODS: This was a cardiovascular substudy within a UK multicenter, placebo-controlled trial, in which 135 women with a singleton pregnancy and severe early-onset FGR (defined as a combination of estimated fetal weight or abdominal circumference below the 10th centile and absent/reversed end-diastolic flow in the umbilical artery on Doppler velocimetry, diagnosed between 22 + 0 and 29 + 6 weeks' gestation) were assigned randomly to receive either 25 mg sildenafil three times daily or placebo until 32 + 0 weeks' gestation or delivery. Maternal blood pressure (BP), heart rate (HR), augmentation index, pulse wave velocity (PWV), cardiac output, stroke volume (SV) and total peripheral resistance were recorded before randomization, 1-2 h and 48-72 h post-randomization, and 24-48 h postnatally. For continuous data, analysis was performed using repeated measures ANOVA methods including terms for timepoint, treatment allocation and their interaction. RESULTS: Included were 134 women assigned randomly to sildenafil (n = 69) or placebo (n = 65) who had maternal BP and HR recorded at baseline. At 1-2 h post-randomization, compared with baseline values, sildenafil increased maternal HR by 4 bpm more than did placebo (mean difference, 5.00 bpm (95% CI, 1.00-12.00 bpm) vs 1.25 bpm (95% CI, -5.38 to 7.88 bpm); P = 0.004) and reduced systolic BP by 1 mmHg more (mean difference, -4.13 mmHg (95% CI, -9.94 to 1.44 mmHg) vs -2.75 mmHg (95% CI, -7.50 to 5.25 mmHg); P = 0.048). Even after adjusting for maternal mean arterial pressure, sildenafil reduced aortic PWV by 0.60 m/s more than did placebo (mean difference, -0.90 m/s (95% CI, -1.31 to -0.51 m/s) vs -0.26 m/s (95% CI, -0.75 to 0.59 m/s); P = 0.001). Sildenafil was associated with a non-significantly greater decrease in SV index after 1-2 h post-randomization than was placebo (mean difference, -5.50 mL/m2 (95% CI, -11.00 to -0.50 mL/m2 ) vs 0.00 mL/m2 (95% CI, -5.00 to 4.00 mL/m2 ); P = 0.056). CONCLUSIONS: Sildenafil in a dose of 25 mg three times daily increases HR, reduces BP and reduces arterial stiffness in pregnancies complicated by severe early-onset FGR. These changes are short term, modest and consistent with the anticipated vasodilatory effect. They have no short- or long-term clinical impact on the mother. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A longitudinal, observational study of women who persisted in smoking in successive pregnancies.

BACKGROUND: This longitudinal study examined the profile and pregnancy-related behaviours of women who reported smoking in two successive pregnancies when they presented for prenatal care in a large maternity hospital. METHODS: Using the hospital electronic medical records, women who delivered two successive singleton pregnancies during the years 2011-15 were analyzed. Standardized data were computerized by a midwife at the first prenatal visit, following delivery and before discharge. RESULTS: Over the 5 years, 6647 women delivered twice. Overall 5754 (86.6%) were persistent non-smokers in both pregnancies, 609 (9.2%) were persistent smokers in both pregnancies and between pregnancies 202 (3.0%) quit and 82 (1.2%) started smoking. Compared with persistent non-smokers, persistent smokers had higher rates of reported illicit drug use, alcohol consumption and psychological problems and lower rates of planned pregnancy, folic acid supplementation and breastfeeding in both pregnancies (all P < 0.001). In persistent smokers, folic acid supplementation practices deteriorated and illicit drug use increased in the subsequent pregnancy. CONCLUSIONS: We found that approximately one in 10 women smoked in two consecutive pregnancies. Furthermore, compared with non-smokers, persistent smokers were more likely to report other health behaviours associated with adverse pregnancy outcomes and may require additional multidisciplinary support.

Comparison of survival of stage I-III colon cancer by travel distance and hospital volume.

BACKGROUND: Previous studies have demonstrated improved outcomes at high-volume colorectal surgery centers; however, the benefit for patients who live far from such centers has not been assessed relative to local, low-volume facilities. METHODS: The 2010-2015 National Cancer Database (NCDB) was queried for patients with stage I-III colon adenocarcinoma undergoing treatment at a single center. A 'local, low-volume' cohort was constructed of 12,768 patients in the bottom quartile of travel distance at the bottom quartile of institution surgical volume and a 'travel, high-volume' cohort of 11,349 patients in the top quartile of travel distance at the top quartile of institution surgical volume. RESULTS: In unadjusted analysis, patients in the travel cohort had improved rates of positive resection margins (3.7% vs. 5.5%, p < 0.001), adequate lymph-node harvests (92% vs. 83.6%, p < 0.001), and 30- (2.2% vs. 3.9%, p < 0.001) and 90-day mortality (3.7% vs. 6.4%, p < 0.001). On multivariable logistic regression analysis adjusting for patient demographic, tumor, and facility characteristics, the cohorts demonstrated equivalent overall survival (HR: 0.972, p = 0.39), with improved secondary outcomes in the 'travel' cohort of adequate lymph-node harvesting (OR: 0.57, p < 0.001), and 30- (OR 0.79, p = 0.019) and 90-day mortality (OR 0.80, p = 0.004). CONCLUSIONS: For patients with stage I-III colon cancer, traveling to high-volume institutions compared to local, low-volume centers does not convey an overall survival benefit. However, given advantages including 30- and 90-day mortality and adequate lymph-node harvest, nuanced patient recommendations should consider both these differences and the unquantified benefits to local care, including cost, travel time, and support systems.

Experimental Observation of Plasma Wakefield Growth Driven by the Seeded Self-Modulation of a Proton Bunch.

We measure the effects of transverse wakefields driven by a relativistic proton bunch in plasma with densities of 2.1×10^{14} and 7.7×10^{14} electrons/cm^{3}. We show that these wakefields periodically defocus the proton bunch itself, consistently with the development of the seeded self-modulation process. We show that the defocusing increases both along the bunch and along the plasma by using time resolved and time-integrated measurements of the proton bunch transverse distribution. We evaluate the transverse wakefield amplitudes and show that they exceed their seed value (<15 MV/m) and reach over 300 MV/m. All these results confirm the development of the seeded self-modulation process, a necessary condition for external injection of low energy and acceleration of electrons to multi-GeV energy levels.

Electronic Modifications of Fluorescent Cytidine Analogues Control Photophysics and Fluorescent Responses to Base Stacking and Pairing.

The rational design of fluorescent nucleoside analogues is greatly hampered by the lack of a general method to predict their photophysics, a problem that is especially acute when base pairing and stacking change fluorescence. To better understand these effects, a series of tricyclic cytidine (tC and tCO ) analogues ranging from electron-rich to electron-deficient was designed and synthesized. They were then incorporated into oligonucleotides, and photophysical responses to base pairing and stacking were studied. When inserted into double-stranded DNA oligonucleotides, electron-rich analogues exhibit a fluorescence turn-on effect, in contrast with the electron-deficient compounds, which show diminished fluorescence. The magnitude of these fluorescence changes is correlated with the oxidation potential of nearest neighbor nucleobases. Moreover, matched base pairing enhances fluorescence turn-on for the electron-rich compounds, and it causes a fluorescence decrease for the electron-deficient compounds. For the tCO compounds, the emergence of vibrational fine structure in the fluorescence spectra in response to base pairing and stacking was observed, offering a potential new tool for studying nucleic acid structure and dynamics. These results, supported by DFT calculations, help to rationalize fluorescence changes in the base stack and will be useful for selecting the best fluorescent nucleoside analogues for a desired application.