Characterisation of formulated high-density poly(ethylene) by magic angle spinning nuclear magnetic resonance.

High-density poly(ethylene) (HDPE) is an important class of polymer used extensively in plastic packaging as well as numerous other applications. HDPE has a structure that consists of crystalline (monoclinic and orthorhombic) and amorphous domains. Here, we exploit a range of approaches focusing on magic angle spinning (MAS) nuclear magnetic resonance (NMR) aimed at comparing the effect of the HDPE sample formulation (cutting, shaving and cryomilling), from the commercially available manufactured pellets, into these domains and their quantification. 13C cross polarisation (CP) experiments reveal that these formulated HDPEs are qualitatively different and 13C CP build-up curves and 13C direct excitation experiments enable the content of each domain to be obtained, pointing to an increase of monoclinic domain at the expense of the orthorhombic one upon increased processing. The crystallinity contents obtained compared, in some cases, favourably with those obtained by differential scanning calorimetry (DSC) data. These results provide evidence that the manner of preparation of HDPE pellets modifies the concentration of the various domains and suggest that care should be taken during processing.

Studying Surface Chemistry of Mixed Conducting Perovskite Oxide Electrodes with Synchrotron-Based Soft X-rays.

A fundamental understanding of the electrochemical reactions and surface chemistry at the solid-gas interface in situ and operando is critical for electrode materials applied in electrochemical and catalytic applications. Here, the surface reactions and surface composition of a model of mixed ionic and electronic conducting (MIEC) perovskite oxide, (La0.8Sr0.2)0.95Cr0.5Fe0.5O3-δ (LSCrF8255), were investigated in situ using synchrotron-based near-ambient pressure (AP) X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine-structure spectroscopy (NEXAFS). The measurements were conducted with a surface temperature of 500 °C under 1 mbar of dry oxygen and water vapor, to reflect the implementation of the materials for oxygen reduction/evolution and H2O electrolysis in the applications such as solid oxide fuel cell (SOFC) and electrolyzers. Our direct experimental results demonstrate that, rather than the transition metal (TM) cations, the surface lattice oxygen is the significant redox active species under both dry oxygen and water vapor environments. It was proven that the electron holes formed in dry oxygen have a strong oxygen character. Meanwhile, a relatively higher concentration of surface oxygen vacancies was observed on the sample measured in water vapor. We further showed that in water vapor, the adsorption and dissociation of H2O onto the perovskite surface were through forming hydroxyl groups. In addition, the concentration of Sr surface species was found to increase over time in dry oxygen due to Sr surface segregation, with the presence of oxygen holes on the surface serving as an additional driving force. Comparatively, less Sr contents were observed on the sample in water vapor, which could be due to the volatility of Sr(OH)2. A secondary phase was also observed, which exhibited an enrichment in B-site cations, particularly in Fe and relatively in Cr, and a deficiency in A-site cation, notably in La and relatively in Sr. The findings and methodology of this study allow for the quantification of surface defect chemistry and surface composition evolution, providing crucial understanding and design guidelines in the electrocatalytic activity and durability of electrodes for efficient conversions of energy and fuels.

Spatial and seasonal controls on dissolved organic matter composition in shallow aquifers under the rapidly developing city of Patna, India.

The distribution and composition of dissolved organic matter (DOM) affects numerous (bio)geochemical processes in environmental matrices including groundwater. This study reports the spatial and seasonal controls on the distribution of groundwater DOM under the rapidly developing city of Patna, Bihar (India). Major DOM constituents were determined from river and groundwater samples taken in both pre- and post-monsoon seasons in 2019, using excitation-emission matrix (EEM) fluorescence spectroscopy. We compared aqueous fluorescent DOM (fDOM) composition to satellite-derived land use data across the field area, testing the hypothesis that the composition of groundwater DOM, and particularly the components associated with surface-derived ingress, may be controlled, in part, by land use. In the pre-monsoon season, the prominence of tryptophan-like components likely generated from recent biological activity overwhelmed the humic-like and tyrosine-like fluorescence signals. Evidence from fluorescence data suggest groundwater in the post-monsoon season is composed of predominantly i) plant-derived matter and ii) anthropogenically influenced DOM (e.g. tryptophan-like components). Organic tracers, as well as Eh and Cl-, suggest monsoonal events mobilise surface-derived material from the unsaturated zone, causing dissolved organic carbon (DOC) of more microbial nature to infiltrate to >100 m depth. A correlation between higher protein:humic-like fluorescence and lower vegetation index (NDVI), determined from satellite-based land use data, in the post-monsoon season, indicates the ingression of wastewater-derived OM in groundwater under the urban area. Attenuated protein:humic-like fluorescence in groundwater close to the river points towards the mixing of groundwater and river water. This ingress of surface-derived OM is plausibly exacerbated by intensive groundwater pumping under these areas. Our approach to link the composition of aqueous organics with land use could easily be adapted for similar hydrogeochemical settings to determine the factors controlling groundwater DOM composition in various contexts.

Automated Detection of Patients at High Risk of Polypharmacy including Anticholinergic and Sedative Medications.

Ensuring that medicines are prescribed safely is fundamental to the role of healthcare professionals who need to be vigilant about the risks associated with drugs and their interactions with other medicines (polypharmacy). One aspect of preventative healthcare is to use artificial intelligence to identify patients at risk using big data analytics. This will improve patient outcomes by enabling pre-emptive changes to medication on the identified cohort before symptoms present. This paper presents a mean-shift clustering technique used to identify groups of patients at the highest risk of polypharmacy. A weighted anticholinergic risk score and a weighted drug interaction risk score were calculated for each of 300,000 patient records registered with a major regional UK-based healthcare provider. The two measures were input into the mean-shift clustering algorithm and this grouped patients into clusters reflecting different levels of polypharmaceutical risk. Firstly, the results showed that, for most of the data, the average scores are not correlated and, secondly, the high risk outliers have high scores for one measure but not for both. These suggest that any systematic recognition of high-risk groups should consider both anticholinergic and drug-drug interaction risks to avoid missing high-risk patients. The technique was implemented in a healthcare management system and easily and automatically identifies groups at risk far faster than the manual inspection of patient records. This is much less labour-intensive for healthcare professionals who can focus their assessment only on patients within the high-risk group(s), enabling more timely clinical interventions where necessary.

Structure of Rhizobium sp. 4-9 histamine dehydrogenase and analysis of the electron transfer pathway to an abiological electron acceptor.

Histamine dehydrogenase from the gram-negative bacterium Rhizobium sp. 4-9 (HaDHR) is a member of a small family of dehydrogenases containing a covalently attached FMN, and the only member so far identified to date that does not exhibit substrate inhibition. In this study, we present the 2.1 Å resolution crystal structure of HaDHR. This new structure allowed for the identification of the internal electron transfer pathway to abiological ferrocene-based mediators. Alanine 437 was identified as the exit point of electrons from the Fe4S4 cluster. The enzyme was modified with a Ser436Cys mutation to facilitate covalent attachment of a ferrocene moiety. When modified with Fc-maleimide, this new construct demonstrated direct electron transfer from the enzyme to a gold electrode in a histamine concentration-dependent manner without the need for any additional electron mediators.

Surface Decorations on Mixed Ionic and Electronic Conductors: Effects on Surface Potential, Defects, and the Oxygen Exchange Kinetics.

The oxygen exchange kinetics of epitaxial Pr0.1Ce0.9O2-δ electrodes was modified by decoration with submonolayer amounts of different basic (SrO, CaO) and acidic (SnO2, TiO2) binary oxides. The oxygen exchange reaction (OER) rate and the total conductivity were measured by in situ PLD impedance spectroscopy (i-PLD), which allows to directly track changes of electrochemical properties after each deposited pulse of surface decoration. The surface chemistry of the electrodes was investigated by near-ambient pressure XPS measurements (NAP-XPS) at elevated temperatures and by low-energy ion scattering (LEIS). While a significant alteration of the OER rate was observed after decoration with binary oxides, the pO2 dependence of the surface exchange resistance and its activation energy were not affected, suggesting that surface decorations do not alter the fundamental OER mechanism. Furthermore, the total conductivity of the thin films does not change upon decoration, indicating that defect concentration changes are limited to the surface layer. This is confirmed by NAP-XPS measurements which find only minor changes of the Pr-oxidation state upon decoration. NAP-XPS was further employed to investigate changes of the surface potential step on decorated surfaces. From a mechanistic point of view, our results indicate a correlation between the surface potential and the altered oxygen exchange activity. Oxidic decorations induce a surface charge which depends on their acidity (acidic oxides lead to a negative surface charge), affecting surface defect concentrations, any existing surface potential step, potentially adsorption dynamics, and consequently also the OER kinetics.

Electronic and ionic effects of sulphur and other acidic adsorbates on the surface of an SOFC cathode material.

The effects of sulphur adsorbates and other typical solid oxide fuel cell (SOFC) poisons on the electronic and ionic properties of an SrO-terminated (La,Sr)CoO3 (LSC) surface and on its oxygen exchange kinetics have been investigated experimentally with near ambient pressure X-ray photoelectron spectroscopy (NAP-XPS), low energy ion scattering (LEIS) and impedance spectroscopy as well as computationally with density functional theory (DFT). The experiment shows that trace amounts of sulphur in measurement atmospheres form SO2- 4 adsorbates and strongly deactivate a pristine LSC surface. They induce a work function increase, indicating a changing surface potential and a surface dipole. DFT calculations reveal that the main participants in these charge transfer processes are not sub-surface transition metals, but surface oxygen atoms. The study further shows that sulphate adsorbates strongly affect oxygen vacancy formation energies in the LSC (sub-)surface, thus affecting defect concentrations and oxygen transport properties. To generalize these results, the investigation was extended to other acidic oxides which are technologically relevant as SOFC cathode poisons, such as CO2 and CrO3. The results unveil a clear correlation of work function changes and redistributed charge with the Smith acidity of the adsorbed oxide and clarify fundamental mechanistic details of atomic surface modifications. The impact of acidic adsorbates on various aspects of the oxygen exchange reaction rate is discussed in detail.

Emerging organic contaminants in the River Ganga and key tributaries in the middle Gangetic Plain, India: Characterization, distribution & controls.

The presence and distribution of emerging organic contaminants (EOCs) in freshwater environments is a key issue in India and globally, particularly due to ecotoxicological and potential antimicrobial resistance concerns. Here we have investigated the composition and spatial distribution of EOCs in surface water along a ∼500 km segment of the iconic River Ganges (Ganga) and key tributaries in the middle Gangetic Plain of Northern India. Using a broad screening approach, in 11 surface water samples, we identified 51 EOCs, comprising of pharmaceuticals, agrochemicals, lifestyle and industrial chemicals. Whilst the majority of EOCs detected were a mixture of pharmaceuticals and agrochemicals, lifestyle chemicals (and particularly sucralose) occurred at the highest concentrations. Ten of the EOCs detected are priority compounds (e.g. sulfamethoxazole, diuron, atrazine, chlorpyrifos, perfluorooctane sulfonate (PFOS), perfluorobutane sulfonate, thiamethoxam, imidacloprid, clothianidin and diclofenac). In almost 50% of water samples, sulfamethoxazole concentrations exceeded predicted no-effect concentrations (PNECs) for ecological toxicity. A significant downstream reduction in EOCs was observed along the River Ganga between Varanasi (Uttar Pradesh) and Begusarai (Bihar), likely reflecting dilution effects associated with three major tributaries, all with considerably lower EOC concentrations than the main Ganga channel. Sorption and/or redox controls were observed for some compounds (e.g. clopidol), as well as a relatively high degree of mixing of EOCs within the river. We discuss the environmental relevance of the persistence of several parent compounds (notably atrazine, carbamazepine, metribuzin and fipronil) and associated transformation products. Associations between EOCs and other hydrochemical parameters including excitation emission matrix (EEM) fluorescence indicated positive, significant, and compound-specific correlations between EOCs and tryptophan-, fulvic- and humic-like fluorescence. This study expands the baseline characterization of EOCs in Indian surface water and contributes to an improved understanding of the potential sources and controls on EOC distribution in the River Ganga and other large river systems.

The Rationale for Radiation Therapy in Alzheimer's Disease.

Alzheimer's Disease (AD) represents a major health problem without effective treatments. As the incidence of the disease will continue to rise, it is imperative to find new treatment options to halt or slow disease progression. In recent years, several groups have begun to study the utility of low total dose radiation therapy (LTDRT) to inhibit some of the pathological features of AD and improve cognition in a variety of animal models. These preclinical studies have led to Phase 1 and 2 trials in different centers around the world. In this review, we present and interpret the pre-clinical evidence report some preliminary clinical data from a Phase 2 trial in early-stage AD patients.

Low-Dose Whole Brain Radiation Therapy for Alzheimer's Dementia: Results From a Pilot Trial in Humans.

PURPOSE: We report neurocognitive, imaging, ophthalmologic, and safety outcomes following low-dose whole brain radiation therapy (LD-WBRT) for patients with early Alzheimer dementia (eAD) treated in a pilot trial. METHODS AND MATERIALS: Trial-enrolled patients were at least 55 years of age, had eAD meeting NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) Alzheimer's Criteria with confirmatory fluorodeoxyglucose and florbetapir positron emission tomography findings; had the capacity to complete neurocognitive function, psychological function, and quality-of-life assessments; had a Rosen modified Hachinski score ≤4; and had estimated survival >12 months. RESULTS: Five patients were treated with LD-WBRT (2 Gy × 5 over 1 week; 3 female; mean age, 73.2 years [range, 69-77]). Four of 5 patients had improved (n = 3) or stable (n = 1) Mini-Mental State Examination (second edition) T-scores at 1 year. The posttreatment scores of all 3 patients who improved increased to the average range. There were additional findings of stability of naming and other cognitive skills as well as stability to possible improvement in imaging findings. No safety issues were encountered. The only side effect was temporary epilation with satisfactory hair regrowth. CONCLUSIONS: Our results from 5 patients with eAD treated with LD-WBRT (10 Gy in 5 fractions) demonstrate a positive safety profile and provide preliminary, hypothesis-generating data to suggest that this treatment stabilizes or improves cognition. These findings will require further evaluation in larger, definitive, randomized trials.

Longitudinal Changes in Body Composition and Resting Metabolic Rate in Male Professional Flat Jockeys: Preliminary Outcomes and Implications for Future Research Directions.

Jockeys are unique given that they make weight daily and, therefore, often resort to fasting and dehydration. Through increasing daily food frequency (during energy deficit), we have reported short-term improvements in jockey's body composition. While these changes were observed over 6-12 weeks with food provided, it is unclear whether such improvements can be maintained over an extended period during free-living conditions. We, therefore, assessed jockeys over 5 years using dual X-ray absorptiometry, resting metabolic rate, and hydration measurements. Following dietary and exercise advice, jockeys reduced fat mass from baseline of 7.1 ± 1.4 kg to 6.1 ± 0.7 kg and 6.1 ± 0.6 kg (p < .001) at Years 1 and 5, respectively. In addition, fat-free mass was maintained with resting metabolic rate increasing significantly from 1,500 ± 51 kcal/day at baseline to 1,612 ± 95 kcal/day and 1,620 ± 92 kcal/day (p < .001) at Years 1 and 5, respectively. Urine osmolality reduced from 816 ± 236 mOsmol/L at baseline to 564 ± 175 mOsmol/L and 524 ± 156 mOsmol/L (p < .001) at Years 1 and 5, respectively. The percent of jockeys consuming a regular breakfast significantly increased from 48% at baseline to 83% (p = .009) and 87% (p = .003) at Years 1 and 5, alongside regular lunch from 35% to 92% (p < .001) and 96% (p < .001) from baseline to Years 1 and 5, respectively. In conclusion, we report that improved body composition can be maintained in free-living jockeys over a 5-year period when appropriate guidance has been provided.

Roadmap for precision preclinical x-ray radiation studies.

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.

Investigation of the physiological response of radiation-induced cystitis patients using hyperbaric oxygen.

Introduction: In this pilot study we have taken a novel functional approach to assess whether differences exist in the activity of key genes involved in the response to radiation and oxidative stress between patients with radiation cystitis. Materials and methods: Arm 1 consisted of patients who had previously been treated for prostate cancer and who had received definitive radiation treatment and had subsequently developed cystitis and/or proctitis and were being treated by hyperbaric oxygen (HBO). Arm 2 consisted of patients who had never been treated by radiation but who were scheduled for HBO treatment for another pathology. The genes chosen for the study were HMOX1, NOS2, SOD2, TNFα, IL-6 and TGFß. Blood and urine was collected pre and post HBO treatment. Results: Gene expression showed a significant difference in NOS2 (p = 0.0178) and TNFα (p = 0.037) between the control and cystitis patients. The plasma levels of VEGF-A were significantly elevated in cystitis patients and there was a strong trend for significant overexpression in urine. Comparing pre and post-dive samples showed little difference in both groups of patients except for VEGF-A which was reduced after the dive in plasma from cystitis patients. Conclusions: This study uncovered some physiological differences in patients with radiation-induced cystitis using HBO treatment as a stimulus to induce mild oxidative stress. Further research is ongoing to assess whether the acute exposure to HBO might be a physiological screening tool to identify patients susceptible to chronic radiation toxicity.

Precursor engineering of hydrotalcite-derived redox sorbents for reversible and stable thermochemical oxygen storage.

Chemical looping processes based on multiple-step reduction and oxidation of metal oxides hold great promise for a variety of energy applications, such as CO2 capture and conversion, gas separation, energy storage, and redox catalytic processes. Copper-based mixed oxides are one of the most promising candidate materials with a high oxygen storage capacity. However, the structural deterioration and sintering at high temperatures is one key scientific challenge. Herein, we report a precursor engineering approach to prepare durable copper-based redox sorbents for use in thermochemical looping processes for combustion and gas purification. Calcination of the CuMgAl hydrotalcite precursors formed mixed metal oxides consisting of CuO nanoparticles dispersed in the Mg-Al oxide support which inhibited the formation of copper aluminates during redox cycling. The copper-based redox sorbents demonstrated enhanced reaction rates, stable O2 storage capacity over 500 redox cycles at 900 °C, and efficient gas purification over a broad temperature range. We expect that our materials design strategy has broad implications on synthesis and engineering of mixed metal oxides for a range of thermochemical processes and redox catalytic applications.

Environmental tracers and groundwater residence time indicators reveal controls of arsenic accumulation rates beneath a rapidly developing urban area in Patna, India.

Groundwater security is a pressing environmental and societal issue, particularly due to significantly increasing stressors on water resources, including rapid urbanization and climate change. Groundwater arsenic is a major water security and public health challenge impacting millions of people in the Gangetic Basin of India and elsewhere globally. In the rapidly developing city of Patna (Bihar) in northern India, we have studied the evolution of groundwater chemistry under the city following a three-dimensional sampling framework of multi-depth wells spanning the central urban zone in close proximity to the River Ganges (Ganga) and transition into peri-urban and rural areas outside city boundaries and further away from the river. Using inorganic geochemical tracers (including arsenic, iron, manganese, nitrate, nitrite, ammonium, sulfate, sulfide and others) and residence time indicators (CFCs and SF6), we have evaluated the dominant hydrogeochemical processes occurring and spatial patterns in redox conditions across the study area. The distribution of arsenic and other redox-sensitive parameters is spatially heterogenous, and elevated arsenic in some locations is consistent with arsenic mobilization via reductive dissolution of iron hydroxides. Residence time indicators evidence modern (<~60-70 years) groundwater and suggest important vertical and lateral flow controls across the study area, including an apparent seasonal reversal in flow regimes near the urban center. An overall arsenic accumulation rate is estimated to be ~0.003 ± 0.003 µM.yr-1 (equivalent to ~0.3 ± 0.2 µg.yr-1), based on an average of CFC-11, CFC-12 and SF6-derived models, with the highest rates of arsenic accumulation observed in shallow, near-river groundwaters also exhibiting elevated concentrations of nutrients including ammonium. Our findings have implications on groundwater management in Patna and other rapidly developing cities, including potential future increased groundwater vulnerability associated with surface-derived ingress from large-scale urban abstraction or in higher permeability zones of river-groundwater connectivity.

Low-Temperature Exsolution of Ni-Ru Bimetallic Nanoparticles from A-Site Deficient Double Perovskites.

Exsolution of stable metallic nanoparticles for use as efficient electrocatalysts has been of increasing interest for a range of energy technologies. Typically, exsolved nanoparticles show higher thermal and coarsening stability compared to conventionally deposited catalysts. Here, A-site deficient double perovskite oxides, La2- x NiRuO6- δ (x = 0.1 and 0.15), are designed and subjected to low-temperature reduction leading to exsolution. The reduced double perovskite materials are shown to exsolve nanoparticles of 2-6 nm diameter during the reduction in the low-temperature range of 350-450 °C. The nanoparticle sizes are found to increase after reduction at the higher temperature (450 °C), suggesting diffusion-limited particle growth. Interestingly, both nickel and ruthenium are co-exsolved during the reduction process. The formation of bimetallic nanoparticles at such low temperatures is rare. From the in situ impedance spectroscopy measurements of the double perovskite electrode layers, the onset of the exsolution process is found to be within the first few minutes of the reduction reaction. In addition, the area-specific resistance of the electrode layers is found to decrease by 90% from 291 to 29 Ω cm2 , suggesting encouraging prospects for these low-temperature rapidly exsolved Ni/Ru alloy nanoparticles in a range of catalytic applications.

Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy.

BACKGROUND: Bone-marrow-derived haematopoietic stem and progenitor cells (HSPCs) are a prominent part of the highly complex tumour microenvironment (TME) where they localise within tumours and maintain haematopoietic potency. Understanding the role HSPCs play in tumour growth and response to radiation therapy (RT) may lead to improved patient treatments and outcomes. METHODS: We used a mouse model of non-small cell lung carcinoma where tumours were exposed to RT regimens alone or in combination with GW2580, a pharmacological inhibitor of colony stimulating factor (CSF)-1 receptor. RT-PCR, western blotting and immunohistochemistry were used to quantify expression levels of factors that affect HSPC differentiation. DsRed+ HSPC intratumoural activity was tracked using flow cytometry and confocal microscopy. RESULTS: We demonstrated that CSF-1 is enhanced in the TME following exposure to RT. CSF-1 signaling induced intratumoural HSPC differentiation into M2 polarised tumour-associated macrophages (TAMs), aiding in post-RT tumour survival and regrowth. In contrast, hyperfractionated/pulsed radiation therapy (PRT) and GW2580 ablated this process resulting in improved tumour killing and mouse survival. CONCLUSIONS: Tumours coopt intratumoural HSPC fate determination via CSF-1 signaling to overcome the effects of RT. Thus, limiting intratumoural HSPC activity represents an attractive strategy for improving the clinical treatment of solid tumours.

Correlation between tumor voxel dose response matrix and tumor biomarker profile in patients with head and neck squamous cell carcinoma.

BACKGROUND: We have developed a novel imaging analysis procedure that is highly predictive of local failure after chemoradiation in head and neck cancer. In this study we investigated whether any pretreatment biomarkers correlated with key imaging parameters. METHODS: Pretreatment biopsy material was available for 28 patients entered into an institutional trial of adaptive radiotherapy in which FDG-PET images were collected weekly during treatment. The biopsies were immunohistochemically stained for CD44, EGFR, GLUT1, ALDH1, Ki-67 and p53 and quantified using image analysis. Expression levels were correlated with previously derived imaging parameters, the pretreatment SUVmax and the dose response matrix (DRM). RESULTS: The different parameters of the SUVmax and DRM did not correlate with each other. We observed a positive and highly significant (p = 0.0088) correlation between CD44 expression and volume of tumor with a DRM greater than 0.8. We found no correlation between any DRM parameter and GLUT1, p53, Ki-67 and EGFR or ALDH1. GLUT1 expression did correlate with the maximum SUV0 and the volume of tumor with an SUV0 greater than 20. CONCLUSIONS: The pretreatment SUVmax and DRM are independent imaging parameters that combine to predict local recurrence. The significant correlation between CD44 expression, a known cancer stem cell (CSC) marker, and volume of tumor with a DRM greater than 0.8 is consistent with concept that specific foci of cells are responsible for tumor recurrence and that CSCs may be randomly distributed in tumors in specific niches. Dose painting these small areas may lead to improved tumor control.