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Abstract Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Background: Airway management is a core component of the treatment of cardiac arrest. Where a rescuer cannot establish a patent airway to provide oxygenation and ventilation using standard basic and advanced airway techniques, there may be a need to consider emergency front-of-neck airway access (eFONA, e.g., cricothyroidotomy), but there is limited evidence to inform this approach. Objectives: This scoping review aims to identify the evidence for the use of eFONA techniques in patients with cardiac arrest. Methods: In November 2023, we searched Medline, Embase, and Cochrane Central to identify studies on eFONA in adults. We included randomised controlled trials, non-randomised studies, and case series with at least five cases that described any use of eFONA. We extracted data, including study setting, population characteristics, intervention characteristics, and outcomes. Our analysis focused on four key areas: incidence of eFONA, eFONA success rates, clinical outcomes, and complications. Results: The search identified 21,565 papers, of which 18,934 remained after de-duplication. After screening, we included 69 studies (53 reported incidence, 40 reported success rate, 38 reported clinical outcomes; 36 studies reported complications). We identified only one randomised controlled trial. Across studies, there was a total of 4,457 eFONA attempts, with a median of 31 attempts (interquartile range 16–56.5) per study. There was marked heterogeneity across studies that precluded any pooling of data. There were no studies that included only patients in cardiac arrest. Conclusion: The available evidence for eFONA is extremely heterogeneous, with no studies specifically focusing on its use in adults with cardiac arrest.

Mild traumatic brain injury (mTBI) accounts for over one million emergency visits each year in the United States. The large-scale structural and functional network connectivity changes of mTBI are still unknown. This study was designed to determine the connectome-scale brain network connectivity changes in mTBI at both structural and functional levels. 40 mTBI patients at the acute stage and 50 healthy controls were recruited. A novel approach called Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOLs) was applied for connectome-scale analysis of both diffusion tensor imaging and resting state functional MRI data. Among 358 networks identified on DICCCOL analysis, 41 networks were identified as structurally discrepant between patient and control groups. The involved major white matter tracts include the corpus callosum, and superior and inferior longitudinal fasciculi. Functional connectivity analysis identified 60 connectomic signatures that differentiate patients from controls with 93.75% sensitivity and 100% specificity. Analysis of functional domains showed decreased intra-network connectivity within the emotion network and among emotion-cognition interactions, and increased interactions among action-emotion and action-cognition as well as within perception networks. This work suggests that mTBI may result in changes of structural and functional connectivity on a connectome scale at the acute stage.

Background In 2002, the out‐of‐hospital cardiac arrest (OHCA) survival rate in Detroit was the lowest in the nation. Concerted efforts sought to improve the city's chain of survival with a focus on emergency medical services (EMS). This study assesses the impact on OHCA survival rates and describe factors associated with survival. Methods and Results Data for non‐traumatic OHCA cases in Detroit from 2014 to 2016 were extracted from CARES (Cardiac Arrest Registry to Enhance Survival). Chi‐squared tests, non‐parametric tests, and a multivariable logistic regression analysis were employed to examine the associations between overall survival and its covariates. A total of 2359 non‐traumatic OHCA cases were examined. The overall survival rate increased from 3.7% in 2014 to 5.4% in 2015, and 6.4% in 2016 (P

Introduction: The incidence of emergency department (ED) visits for Traumatic Brain Injury (TBI)in the United States exceeds 1,000,000 cases/year with the vast majority classified as mild (mTBI).Using existing computed tomography (CT) decision rules for selecting patients to be referred for CT,such as the New Orleans Criteria (NOC), approximately 70% of those scanned are found to havea negative CT. This study investigates the use of quantified brain electrical activity to assess itspossible role in the initial screening of ED mTBI patients as compared to NOC.Methods: We studied 119 patients who reported to the ED with mTBI and received a CT. Using ahand-held electroencephalogram (EEG) acquisition device, we collected data from frontal leadsto determine the likelihood of a positive CT. The brain electrical activity was processed off-line togenerate an index (TBI-Index, biomarker). This index was previously derived using an independentpopulation, and the value found to be sensitive for significant brain dysfunction in TBI patients. Wecompared this performance of the TBI-Index to the NOC for accuracy in prediction of positive CTfindings.Results: Both the brain electrical activity TBI-Index and the NOC had sensitivities, at 94.7% and92.1% respectively. The specificity of the TBI-Index was more than twice that of NOC, 49.4%and 23.5% respectively. The positive predictive value, negative predictive value and the positivelikelihood ratio were better with the TBI-Index. When either the TBI-Index or the NOC are positive(combining both indices) the sensitivity to detect a positive CT increases to 97%.Conclusion: The hand-held EEG device with a limited frontal montage is applicable to the EDenvironment and its performance was superior to that obtained using the New Orleans criteria.This study suggests a possible role for an index of brain function based on EEG to aid in the acuteassessment of mTBI patients.

Transcatheter aortic valve replacement (TAVR) has undergone rapid expansion, emerging as a viable therapeutic option for low-risk patients in lieu of surgical aortic valve replacement. This paper aims to provide a review of the scientific evidence concerning TAVR in low-risk patients, encompassing both observational and clinical trial data. Furthermore, a substantial proportion of low-risk patients possesses a bicuspid aortic valve, necessitating careful examination of the pertinent anatomic and clinical considerations to TAVR that is highlighted in this review. Additionally, the review expands upon some of the unique challenges associated with alternate access in low-risk patients evaluated for TAVR. Last, this review outlines the pivotal role of a multidisciplinary heart team approach in the execution of all TAVR procedures and the authors’ vision of ‘minimalist TAVR’ as a new era in low-risk TAVR.

Abstract Scenarios have been an important integrating element in the Sixth Assessment Report (AR6) of the Intergovernmental Panel on Climate Change (IPCC) in the understanding of possible climate outcomes, impacts and risks, and mitigation futures. Integration supports a consistent, coherent assessment, new insights and the opportunity to address policy-relevant questions that would not be possible otherwise, for example, which impacts are unavoidable, which are reversible, what is a consistent remaining carbon budget to keep temperatures below a level and what would be a consistent route of action to achieve that goal. The AR6 builds on community frameworks that are developed to support a coherent use of scenarios across the assessment, yet their use in the assessment and the related timelines presented coordination challenges. From lessons within each Working Group (WG) assessment and the cross-WG experience, we present insights into the role of scenarios in future assessments, including the enhanced integration of impacts into scenarios, near-term information and community coordination efforts. Recommendations and opportunities are discussed for how scenarios can support strengthened consistency and policy relevance in the next IPCC assessment cycle.

Summary: Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

Background Studies have demonstrated the efficacy of Palbociclib (CDK 4/6 inhibitor), Gedatolisib (PI3K/mTOR dual inhibitor) and PD0325901 (MEK1/2 inhibitor) in colorectal cancer (CRC), however single agent therapeutics are often limited by the development of resistance. Methods We compared the anti-proliferative effects of the combination of Gedatolisib and Palbociclib and Gedatolisib and PD0325901 in five CRC cell lines with varying mutational background and tested their combinations on total and phosphoprotein levels of signaling pathway proteins. Results The combination of Palbociclib and Gedatolisib was superior to the combination of Palbociclib and PD0325901. The combination of Palbociclib and Gedatolisib had synergistic anti-proliferative effects in all cell lines tested [CI range: 0.11–0.69] and resulted in the suppression of S6rp (S240/244), without AKT reactivation. The combination of Palbociclib and Gedatolisib increased BAX and Bcl−2 levels in PIK3CA mutated cell lines. The combination of Palbociclib and Gedatolisib caused MAPK/ERK reactivation, as seen by an increase in expression of total EGFR, regardless of the mutational status of the cells. Conclusion This study shows that the combination of Palbociclib and Gedatolisib has synergistic anti-proliferative effects in both wild-type and mutated CRC cell lines. Separately, the phosphorylation of S6rp may be a promising biomarker of responsiveness to this combination.

Population change is a main driver behind global environmental change, including urban land expansion. In future scenario modeling, assumptions regarding how populations will change locally, despite identical global constraints of Shared Socioeconomic Pathways (SSPs), can have dramatic effects on subsequent regional urbanization. Using a spatial modeling experiment at high resolution (1 km), this study compared how two alternative US population projections, varying in the spatially explicit nature of demographic patterns and migration, affect urban land dynamics simulated by the Spatially Explicit, Long-term, Empirical City development (SELECT) model for SSP2, SSP3, and SSP5. The population projections included: (1) newer downscaled state-specific population (SP) projections inclusive of updated international and domestic migration estimates, and (2) prevailing downscaled national-level projections (NP) agnostic to localized demographic processes. Our work shows that alternative population inputs, even those under the same SSP, can lead to dramatic and complex differences in urban land outcomes. Under the SP projection, urbanization displays more of an extensification pattern compared to the NP projection. This suggests that recent demographic information supports more extreme urban extensification and land pressures on existing rural areas in the US than previously anticipated. Urban land outcomes to population inputs were spatially variable where areas in close spatial proximity showed divergent patterns, reflective of the spatially complex urbanization processes that can be accommodated in SELECT. Although different population projections and assumptions led to divergent outcomes, urban land development is not a linear product of population change but the result of complex relationships between population, dynamic urbanization processes, stages of urban development maturity, and feedback mechanisms. These findings highlight the importance of accounting for spatial variations in the population projections, but also urbanization process to accurately project long-term urban land patterns.

Purpose: Previous studies have reported data on the internal rectal motion of patients with rectal cancer treated in the prone position. With the introduction of intensity modulated techniques, more patients are treated in the more reproducible supine position. Data informing specific margins for this treatment position are sparse, as are data comparing rectal motion characteristics and factors in male and female patients. The purpose of this retrospective study was to quantify and compare the interfractional rectal movement characteristics of male and female patients with rectal cancer treated with long-course chemoradiation therapy in the supine position. The data will aid the generation of internal target volume margins accounting for this organ's internal physiological movements. Methods and Materials: Cone beam computed tomography (CBCT) images were acquired from 19 male and 16 female patients with rectal cancer on the first 3 days of treatment and weekly thereafter. The rectum, bladder, and femoral heads were delineated on the planning CT (PCT) and 6 CBCT for each patient. Overall, 245 images were analyzed. All patients were treated with a full bladder. The rectum was divided into three 5-cm segments (upper, mid, and lower). The motion of the rectum was quantified by documenting the anteroposterior and lateral distances as measured using fixed anatomic landmarks, namely from the anterior aspect of the sacrum and mid-left femoral head, respectively. These measurements were taken at 1-cm intervals from the inferior border of L5 vertebrae. The sigmoid was excluded from these measurements. Estimations of systematic and random physiological movement error were determined and margins were calculated. Results: Two hundred forty-five image sets (19 PCT + 114 CBCT for male, 16 PCT + 96 CBCT for female) on patients who had undergone long-course radiation therapy were analyzed. Rectal tumor location was 31% in the inferior rectum, 46% in the mid rectum, and 23% in the superior rectum. Random rectal motion (mean of the per-patient standard deviation [σ]) was largest for the upper and mid rectum in the anterior direction. There were statistically significant differences in σ between male and female patients in the left lateral motion of the mid and inferior rectum as well as the anterior, posterior, and right motion of the inferior rectum (mid left: P < .0005; lower left: P < .0005; lower posterior: P = .001; lower anterior: P = .032; lower right: P = .001). Suggested internal target volume margin guidelines are therefore nonisotropic and vary per segment of rectum and sex. Conclusions: In our present study, interfractional rectal motion is shown to be significantly different between male and female patients. Our data suggest that the use of asymmetrical sex-specific margins in patients with rectal cancer treated in the supine position should be considered.

Abstract Population concentration and built‐up land expansion are two prominent features of contemporary urbanization. Existing literature on the population aspect of urbanization has mostly focused on national and regional aggregates, and literature on the land development aspect has often relied on spatial case studies of individual cities or their meta‐analyses. Using newly‐available data, here we conduct the first global‐coverage, spatial analysis of the relationship between (changes in) population and built‐up land at multiple spatial scales, and compare to existing common beliefs about urbanization based on individual city studies. We find that population and built‐up land show distinctly different spatial and temporal patterns (with a global correlation coefficient around 0.6). Contrary to common impressions, our results show that during recent decades, developed and developing regions across the world experienced comparable amounts of built‐up land expansion. While meta‐analyses have reported that built‐up land in urban areas expands globally on average twice as fast as population grows, our results show the global change rates of built‐up land and population are similar. Also, most global population, including what national statistics agencies call urban population, reside in areas with low land development levels (which are frequently less than 5% built up). These changes in perspective suggest that urbanization's potential large‐scale impacts may need to be re‐evaluated, and lead to best‐practice recommendations for urbanization modeling and analysis. Especially, the common practice in large‐scale earth system modeling of assuming demographically‐defined urban population resides in areas with medium to high built‐up land development levels should change.

Abstract In patients with challenging femoral vein anatomy, transcatheter patent foramen ovale (PFO) closure can be safely and effectively be done through the jugular veins guided by ICE from the arm. This novel technique can potentially save resources (anesthesia and TEE) and provide an option for patients without a femoral option.

Climate extremes, exposure and vulnerability all contribute to global difference in heatwave risk. Here the authors investigated the inequality in global heatwave risk under both 1.5 and 2 °C scenarios and found that heatwave risk for the poor under 1.5 °C scenario exceeds that risk for the rich under 2 °C scenario.

In September 2017, in a celebrated speech on the future of Europe, French President Emmanuel Macron proposed the idea that Europe should have at least twenty “European universities” of sufficient scale that would allow students to move between different institutions, experience other cultures and take classes in at least two different languages. Speaking in the Sorbonne to an audience of university presidents, diplomats and parliamentarians as well as students, he argued that culture and knowledge is what binds the European Union together and that European universities could uniquely help to “create a sense of belonging” that will be the “strongest cement for Europe”. Countering the apparent fragmentation of European, Macron’s vision is of revival of the values of multiculturalism and multilingualism wherein every young person should “travel the continent to learn other languages” and “unlearn their natural boorish ways”. This Europe, he claimed, “which has lived through so many wars and conflicts: what holds it together is its culture”

Competition in the beverage industry is increasing on all fronts (advertising, price, product proliferation, service, etc.). As a result, distributors need to understand what is important to retailers and assess how they and their competitors are meeting those needs in the supply chain. In this paper a performance system is proposed to assess the distributor-retailer interface based on the integration of a number of concepts including customer service, relationship exchanges, competitive benchmarking, order winners (consumer preference perceptions), and portfolio analysis.Various performance matrices are constructed which indicate the importance level and service effectiveness for categories of service provided to retailers. These importance/ performance matrices provide a basis for distributors to develop marketing strategies for categories of retailers, as well as for individual retailers. [ABSTRACT FROM AUTHOR]

Igivanad arutelud, milles käsitletakse laste kokkupuudet meediatehnoloogiaga, toovad kommunikatsiooni ja meediauuringute suunal esile erimeelsusi ja vaidlusi põhjustanud pikaajalise traditsiooni. Olgugi et meediatarbimise mõju lastele on uuritud juba ringhäälingu algusaegadest peale, on selle üle endiselt vähe teoretiseeritud ja seda on kirjanduses harva käsitletud, samuti on see meediapoliitika debattides pälvinud vaid vähest mõistmist. Laste ja internetiuuringute puhul on vanad vaidlused süvenenud. Lähtudes ühelt poolt hoiatavatest teadetest riskide, ülemäärase arvutikasutuse ja selle kahjuliku mõju kohta ning teiselt poolt kiidu laulust "digimaailma päriselanikele" ja tehnoloogia võimele muuta maailma, seadis EU Kids Online endale eesmärgiks koguda andmeid, mis aitavad luua terviklikumat pilti veebikeskkonnast, milles noored tegutsevad. Siinses artiklis paigutan selle valdkonna tööd ökoloogilisse raamistikku, lähtudes nii Bronfenbrenneri bioökoloogilisest käsitlusviisist, mis on olnud tähtsal kohal uutes lapsepõlve sotsioloogilistes käsitlustes, kui ka üldisemalt defineeritud meediaökoloogia teoreetilisest raamistikust. Viimast seostatakse peamiselt McLuhani ja hiljem Postmani töödega, kus kirjeldatakse meediakeskkonda kui keerulise vastastikuse mõjutamise süsteemi tehnoloogia ja ühiskonna vahel, kus mitmesugused suhtlusviisid ja vahendatud vastastikune mõjutamine kujundavad oluliselt inimkäitumist ja ühiskondlikku elu. Selline vaatenurk on mõningate põletavate probleemidega tegelemisel väga vajalik, kui kõne all on teadusuuringutel põhinev poliitikakujundamine, mis on seotud interneti haldamise ja reguleerimisega ning noorte kaitsmisega internetikeskkonnas. Full text

Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre- or on-treatment factors that predict response to NACRT besides tumour stage and size. We characterised the response of 33 LARC patients to NACRT, collected tumour samples from patients prior to, during and after NACRT, and performed whole exome, transcriptome and high-depth targeted sequencing. The pre-treatment LARC genome was not predictive of response to NACRT. However, in line with the increasing recognition of microbial influence in cancer, RNA analysis of pre-treatment tumours suggested a greater abundance of Fusobacteria in intermediate and poor responders. In addition, we investigated tumour heterogeneity and evolution in response to NACRT. While matched pre-treatment, on-treatment and post-treatment tumours revealed minimal genome evolution overall, we identified cases in which microsatellite instability developed or was selected for during NACRT. Recent research has suggested a role for adaptive mutability to targeted therapy in colorectal cancer cells. We provide preliminary evidence of selection for mismatch repair deficiency in response to NACRT. Furthermore, pre-NACRT genomic landscapes do not predict treatment response but pre-NACRT microbiome characteristics may be informative.

Public textual cyberbullying has become one of the most prevalent issues associated with online safety of young people, particularly on social networks. To address this issue, we argue that the boundaries of what constitutes public textual cyberbullying needs to be first identified and a corresponding linguistically motivated definition needs to be advanced. Thus, we propose a definition of public textual cyberbullying that contains three necessary and sufficient elements: the personal marker, the dysphemistic element and the cyberbullying link between the previous two elements. Subsequently, we argue that one of the cornerstones in the overall process of mitigating the effects of cyberbullying is the design of a cyberbullying lexical database that specifies what linguistic and cyberbullying specific information is relevant to the detection process. In this vein, we propose a novel cyberbullying lexical database based on the definition of public textual cyberbullying. The overall architecture of our cyberbullying lexical database is determined semantically, and, in order to facilitate cyberbullying detection, the lexical entry encapsulates two new semantic dimensions that are derived from our definition: cyberbullying function and cyberbullying referential domain. In addition, the lexical entry encapsulates other semantic and syntactic information, such as sense and syntactic category, information that, not only aids the process of detection, but also allows us to expand the cyberbullying database using WordNet (Miller, 1993).

The harmful effects of bullying and harassment on children have long been of concern to parents, educators, and policy makers. The online world presents a new environment in which vulnerable children can be victimized and a space where perpetrators find new ways to perform acts of harassment. While online bullying is often considered to be an extension of persistent offline behavior, according to EU Kids Online (2011), the most common form of bullying is in person, face-to-face. With the rise in use of mobile Internet technologies, this balance is changing. Increased levels of use and more time spent online accessed through a variety of devices has increased children’s exposure to a range of online risks, including cyberbullying. This article presents the findings of the Net Children Go Mobile project, a cross-national study of children aged 9–16 in seven European countries. The research builds on the work of EU Kids Online and supports the identification of new trends in children’s online experiences of risk and safety. The study finds that while overall levels of bullying have remained relatively static, levels of online bullying have increased, particularly among younger teens. The relationship between cyberbullying and the use of mobile Internet technologies is examined and factors contributing to increased levels of cyberbullying are highlighted.

This paper proposes a complementary approach to the existing works on the history of water policies in the West of the USA. We defend the idea that the history of Western Water is not fully explained by the hegemony of elites, nor is it the result of the conflicts between local populations and political power. Instead, we offer that water policies in the West are shaped by the interaction of a complex institutional architecture, as well as by the profile of the dominant actors in these institutions. Water policy history is extremely linked to the history of the USA’s State. The reconstruction of that history has been possible by using multiple sources (literature review, grey literature, main actors’ personal records, etc.). We also used data coming from the interviews with the actors, ancients and contemporary, from the many public and private institutions that are involved in water management in the USA.

We describe the first documented spillover of bovine tuberculosis from animals into the human population of the United Kingdom since the resurgence of the disease in cattle in the country. This finding suggests that there may be a small risk for transmission to humans, making continued vigilance particularly necessary.

Purpose The benefit of neoadjuvant therapy for tumours above the peritoneal reflection is not clear. The purpose of this study is to demonstrate the feasibility and downstaging of treating locally advanced tumours from high rectum to distal sigmoid with preoperative chemoradiotherapy (CRT). Methods and Materials Seventeen patients with high rectal, recto-sigmoid or distal sigmoid tumours above the peritoneal reflection received neo-adjuvant CRT, selected on MRI findings indicating T4 disease or threatened circumferential resection margin. All patients were administered neoadjuvant chemotherapy, with Oxaliplatin or Mitomycin C and a Fluoropyrimidine. The pelvis received long-course CT-planned conformal RT, 45 Gy in 25 fractions, with a boost of 5.4–9 Gy in 3–5 fractions. Thirteen patients were treated with concomitant oral or intravenous Fluoropyrimidine chemotherapy. Results Median follow-up was 37 months. Overall survival was 82.35% (95% Confidence Interval (CI) 54.7–93.9) and disease free survival 81.25% (95% CI 52.5–93.5). Only 1 patient suffered loco-regional relapse. Chemotherapy regimens were well tolerated, though some patients required dose reductions. Nine patients (52.9%) lowered pathologic disease AJCC stage, i.e. ‘downstaged’. Six patients (35.3%) achieved complete pathological response. Clear margins were attained in all but 1 patient. Three patients were converted from cT4 to ypT3. No patient required a gap during CRT. One patient suffered a grade III acute toxicity, but no grade IV (RTOG). There were 3 grade III and 3 grade IV late toxicities (LENT-SOMA). Conclusions Locally advanced high rectal and recto-sigmoid tumours may be treated with pre-operative CRT with acceptable toxicity, impressive down-staging, and clear surgical margins.

The sensitivity of regional climate to global average radiative forcing and temperature change is important for setting global climate policy targets and designing scenarios. Setting effective policy targets requires an understanding of the consequences exceeding them, even by small amounts, and the effective design of sets of scenarios requires the knowledge of how different emissions, concentrations, or forcing need to be in order to produce substantial differences in climate outcomes. Using an extensive database of climate model simulations, we quantify how differences in global average quantities relate to differences in both the spatial extent and magnitude of climate outcomes at regional (250–1250 km) scales. We show that differences of about 0.3 °C in global average temperature are required to generate statistically significant changes in regional annual average temperature over more than half of the Earth’s land surface. A global difference of 0.8 °C is necessary to produce regional warming over half the land surface that is not only significant but reaches at least 1 °C. As much as 2.5 to 3 °C is required for a statistically significant change in regional annual average precipitation that is equally pervasive. Global average temperature change provides a better metric than radiative forcing for indicating differences in regional climate outcomes due to the path dependency of the effects of radiative forcing. For example, a difference in radiative forcing of 0.5 W m ^−2 can produce statistically significant differences in regional temperature over an area that ranges between 30% and 85% of the land surface, depending on the forcing pathway.