A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer.

BACKGROUND: 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes. PATIENTS AND METHODS: This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment. RESULTS: In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose. CONCLUSIONS: Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.

A scoping review of public building accessibility.

BACKGROUND: The built environment needs to be designed so that all people can participate in the activities they want and need to do. Yet, accessibility is difficult to put into practice, and accessibility issues tend to be overlooked in the building and planning processes. OBJECTIVES: The aim of this scoping review was to summarize the research front in the area of accessibility to public buildings. Specific aims were to identify knowledge gaps, to identify access activities in relation to environmental features and to link to predominant activities in terms of the International Classification of Functioning, Disability and Health (ICF). METHODS: A literature search was performed in PubMed, PsycINFO, Inspec, Embase and Cochrane databases. Articles in English based on original empirical studies investigating accessibility of public buildings for adults aged ≥18 years with functional limitations were considered. RESULTS: Of the 40 articles included, ten involved study participants, while 30 only examined buildings using instruments to assess accessibility. In addition, the psychometric properties were only tested for a few of them. All articles concerned mobility and several visual limitations, while few addressed cognitive or hearing limitations. Ten main access activities were identified, from using parking/drop-off area to exiting building. CONCLUSIONS: By using the ICF and theoretically relating the accessibility problems to activities, the results revealed that there are large knowledge gaps about accessibility to public buildings for older people and people with functional limitations and that there is a need for more methodological considerations in this area of research.

Effects of applying a standardized assessment and evaluation protocol in housing adaptation implementation - results from a quasi-experimental study.

BACKGROUND: Standardized, research-based strategies to guide the implementation and evaluate the effects of housing adaptations (HA) on client outcomes are rare. We hypothesized that, compared to ordinary practice, a standardized assessment and evaluation protocol for HA implementation would better maintain or improve client outcomes over 1 year. METHOD: Using a cluster design, South Swedish municipalities were recruited to an intervention or control group. Data on activities of daily living, usability of the home, health related quality of life, and participation frequency and satisfaction were collected at home visits 1 month before the HA (baseline; T1), and at 3 (T2), 6 (T3) and 12 (T4) months after. In the intervention group (n = 112) data were collected according to a standardized protocol while in the control group (n = 129) ordinary routines were applied. Changes from baseline to subsequent time points were categorized as no deterioration (i.e. improvement or no change) or deterioration, for each outcome item separately. Differences in "no deterioration" between the groups were assessed using logistic regression. RESULTS: Little effect of using the standardized protocol was detected. For activities of daily living, statistically significant differences between the groups were found for toileting (T1-T4; OR 3.14), dressing (T1-T4; OR2.89) and cooking (T1-T3 and T1-T4; OR 3.14). For usability of the home differences were found in personal hygiene (T1-T2; OR 2.32) using a wheelchair (T1-T2 and T1-T3; OR 9.50), picking up the mail (T1-T3; OR 4.06), and in participation, helping others (T1-T3 and T1-T4; OR 2.33 and 3.36). CONCLUSION: The applied standardized protocol for HA implementation did not show any convincing effect, possibly due to the complexity of the intervention itself, and the implementation process. A process evaluation might generate in-depth knowledge about the reasons behind the findings. TRIAL REGISTRATION: ClinicalTrials.gov . NCT01960582.

ACCURATE KAP METER CALIBRATION AS A PREREQUISITE FOR OPTIMISATION IN PROJECTION RADIOGRAPHY.

Modern X-ray units register the air kerma-area product, PKA, with a built-in KAP meter. Some KAP meters show an energy-dependent bias comparable with the maximum uncertainty articulated by the IEC (25 %), adversely affecting dose-optimisation processes. To correct for the bias, a reference KAP meter calibrated at a standards laboratory and two calibration methods described here can be used to achieve an uncertainty of <7 % as recommended by IAEA. A computational model of the reference KAP meter is used to calculate beam quality correction factors for transfer of the calibration coefficient at the standards laboratory, Q0, to any beam quality, Q, in the clinic. Alternatively, beam quality corrections are measured with an energy-independent dosemeter via a reference beam quality in the clinic, Q1, to beam quality, Q Biases up to 35 % of built-in KAP meter readings were noted. Energy-dependent calibration factors are needed for unbiased PKA Accurate KAP meter calibration as a prerequisite for optimisation in projection radiography.

Daily life consequences, cognitive impairment, and fatigue after transient ischemic attack.

OBJECTIVES: Studies suggest that fatigue and cognitive impairment may be present after transient ischemic attack (TIA), but little is known about consequences in daily life. The main aim was to longitudinally explore the presence of fatigue, cognitive impairment, and consequences in daily life including communication after clinically diagnosed TIA at 1 and 9 months after the event. MATERIAL AND METHODS: A consecutive sample of 46 patients (23 women, 69 ± 12.3 years) was assessed at discharge from hospital and at 1 and 9 months after TIA regarding cognition, mental fatigue, tiredness, and activities of daily life. This served as basis for an interview concerning experienced changes related to the TIA. RESULTS: Problems in daily life with probable association with the TIA were experienced by 37% (n = 45) of participants 9 months after the TIA event. Cognitive impairment was present in 40% (n = 44) after 1 month and 30% (n = 23) after 9 months. Mental fatigue was experienced by 26% (n = 42) after 1 month and 17% (n = 39) after 9 months. Communication problems were reported and increased from 7 to 14 participants between the two time points. CONCLUSIONS: A third of the TIA patients experienced problems in performance of complex activities in daily life and often communication problems within the first 9 months. Cognitive impairment and mental fatigue could be factors influencing performance in daily life and at work, but this needs to be verified in a larger sample. The risk of activity limitations indicates need for multiprofessional support and systematic routines for TIA follow-up.

Enabling sense-making for patients receiving outpatient palliative treatment: A participatory action research driven model for person-centered communication.

OBJECTIVES: In clinical palliative cancer care, the diversity of patient concerns over time makes information provision a critical issue, the demands of information-seeking patients presenting a challenge to both the communicative and organizational skills of the health provider. This study puts forward a practice model for communication between patients, their family members, and professional health providers during ongoing palliative chemotherapy; a model which supports the providers in enabling person-centered communication. METHOD: A constant comparative analysis adapted to participatory action research was applied. The model was developed step-wise in three interrelated cycles, with results from previous studies from palliative cancer care processed in relation to professional health providers' experience-based clinical knowledge. In doing this, focus group discussions were carried out with providers and patients to develop and revise the model. RESULTS: The Enabling Sense Making model for person-centered communication gave rise to three domains (which are also the major communicative actors in palliative care): the patient, the family, and the provider. These actors were placed in the context of a communicative arena. The three respective domains were built up in different layers discriminating between significant aspects of person-centered communication, from the manifest that is most usually explicated in dialogues, to the latent that tends to be implicitly mediated. SIGNIFICANCE OF RESULTS: The model intends to facilitate timely reorientation of care from curative treatment or rehabilitation to palliation, as well as the introduction of appropriate palliative interventions over time during palliative phases. In this way the model is to be regarded a frame for directing the awareness of the professionals, which focuses on how to communicate and how to consider the patient's way of reasoning. The model could be used as a complement to other strategic initiatives for the advancement of palliative care communication. It needs to be further evaluated in regard to practice evidence.

AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin.

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

AUTOMATIC SEGMENTATION OF PELVIS FOR BRACHYTHERAPY OF PROSTATE.

Advanced model-based iterative reconstruction algorithms in quantitative computed tomography (CT) perform automatic segmentation of tissues to estimate material properties of the imaged object. Compared with conventional methods, these algorithms may improve quality of reconstructed images and accuracy of radiation treatment planning. Automatic segmentation of tissues is, however, a difficult task. The aim of this work was to develop and evaluate an algorithm that automatically segments tissues in CT images of the male pelvis. The newly developed algorithm (MK2014) combines histogram matching, thresholding, region growing, deformable model and atlas-based registration techniques for the segmentation of bones, adipose tissue, prostate and muscles in CT images. Visual inspection of segmented images showed that the algorithm performed well for the five analysed images. The tissues were identified and outlined with accuracy sufficient for the dual-energy iterative reconstruction algorithm whose aim is to improve the accuracy of radiation treatment planning in brachytherapy of the prostate.

PARALLELISATION OF THE MODEL-BASED ITERATIVE RECONSTRUCTION ALGORITHM DIRA.

New paradigms for parallel programming have been devised to simplify software development on multi-core processors and many-core graphical processing units (GPU). Despite their obvious benefits, the parallelisation of existing computer programs is not an easy task. In this work, the use of the Open Multiprocessing (OpenMP) and Open Computing Language (OpenCL) frameworks is considered for the parallelisation of the model-based iterative reconstruction algorithm DIRA with the aim to significantly shorten the code's execution time. Selected routines were parallelised using OpenMP and OpenCL libraries; some routines were converted from MATLAB to C and optimised. Parallelisation of the code with the OpenMP was easy and resulted in an overall speedup of 15 on a 16-core computer. Parallelisation with OpenCL was more difficult owing to differences between the central processing unit and GPU architectures. The resulting speedup was substantially lower than the theoretical peak performance of the GPU; the cause was explained.

Dental status and self-assessed chewing ability in 70- and 80-year-old subjects in Sweden.

The objective was to compare two cohorts of elderly people, 70 and 80 years old, with respect to dental status and self-assessed chewing ability. The hypotheses were as follows: (i) dental status is associated with self-assessed chewing ability; (ii) chewing ability is poorer among the 80- than the 70-year-old subjects. Identical questionnaires were in 2012 sent to all subjects born in 1942 and 1932, living in two Swedish counties. The response rate was 70.1% resulting in samples of 5697 70- and 2922 80-year-old subjects. Answers to questions on self-assessed chewing ability, dental status and some other factors have been analysed. Dental status varied but was in general good; 72% of the 70- and 60% of the 80-year-old subjects reported that they had all or only few missing teeth. Rate of edentulism was 3% and 7%, respectively. Removable partial dentures were reported by 6% and 10%, respectively, implant treatment by 13% in both cohorts. Self-assessed chewing ability was mostly good and correlated with the number of teeth (Spearman rho = 0.46). A majority of the edentulous subjects assessed their chewing ability as very or fairly good. Logistic regression showed that self-assessed chewing ability was significantly associated with a number of dental variables but also with general health. In conclusion, dental status was relatively good at both ages but somewhat poorer in the older cohort. Dental status, some other dental variables and being healthy were in both age groups significantly associated with self-assessed chewing ability.

In-situ calibration of clinical built-in KAP meters with traceability to a primary standard using a reference KAP meter.

The air kerma-area product (KAP) is used for settings of diagnostic reference levels. The International Atomic Energy Agency (IAEA) recommends that doses in diagnostic radiology (including the KAP values) be estimated with an accuracy of at least ± 7% (k = 2). Industry standards defined by the International Electrotechnical Commission (IEC) specify that the uncertainty of KAP meter measurements should be less than ± 25% (k = 2). Medical physicists willing to comply with the IAEA's recommendation need to apply correction factors to KAP values reported by x-ray units. The aim of this work is to present and evaluate a calibration method for built-in KAP meters on clinical x-ray units. The method is based on (i) a tandem calibration method, which uses a reference KAP meter calibrated to measure the incident radiation, (ii) measurements using an energy-independent ionization chamber to correct for the energy dependence of the reference KAP meter, and (iii) Monte Carlo simulations of the beam quality correction factors that correct for differences between beam qualities at a standard laboratory and the clinic. The method was applied to the KAP meter in a Siemens Aristos FX plus unit. It was found that values reported by the built-in KAP meter differed from the more accurate values measured by the reference KAP meter by more than 25% for high tube voltages (more than 140 kV) and heavily filtered beams (0.3 mm Cu). Associated uncertainties were too high to claim that the IEC's limit of 25% was exceeded. Nevertheless the differences were high enough to justify the need for a more accurate calibration of built-in KAP meters.

Toxicity screening of produced water extracts in a zebrafish embryo assay.

Produced water is the largest effluent discharge from oil and gas/condensate production facilities in the North Sea. There is concern that contaminants originating from the reservoir and chemicals used in the production process may affect marine organisms. Developmental toxicity of extractable organic compounds in produced water effluents from oil and gas/condensate production platforms in the Norwegian sector of the North Sea was assessed in a temporal and spatial manner using zebrafish (Danio rerio) embryos. Large-scale solid-phase extraction (SPE) and on-column fractionation of water-soluble fraction (WSF) and an oil/particulate fraction was used in a rapid screening bioassay for embryotoxicity. Exposure to produced water extracts increased rate of mortality and reduced pigmentation and heart rate, as well as delaying time to hatch. The oil/particulate fraction was 10-fold less toxic than WSF, indicating that toxicity was predominantly produced by moderately polar and bioavailable compounds. Large spatial and temporal variation in produced water toxicity was observed, displaying considerable variability in the reservoir, oil well, and effluent composition over time. The noted toxicity did not correlate well with either reported produced water composition or parameters such as total hydrocarbons, thus challenging chemical measurements as a reliable source of information for predicting complex effects. Although embryotoxicity was observed following exposure to the extracts, dilution and transformation of produced water in the recipient are expected to rapidly reduce the concentrations of compounds in the effluents to levels below the thresholds of observed effects.

Oral bacterial community dynamics in paediatric patients with malignancies in relation to chemotherapy-related oral mucositis: a prospective study.

The role of oral bacteria in the development of chemotherapy-related oral mucositis has not been fully elucidated. This study aimed to investigate oral bacterial community diversity and dynamics in paediatric patients with malignancies in relation to the occurrence of oral mucositis. Patients with malignancies (n = 37) and reference individuals without known systemic disorders (n = 38) were recruited. For patients, oral bacterial samples were taken from mucosal surfaces both at the time of malignancy diagnosis and during chemotherapy. If oral mucositis occurred, samples were taken from the surface of the mucositis lesions. Oral mucosal bacterial samples were also taken from reference individuals. All samples were assessed using a 16S ribosomal RNA gene 454 pyrosequencing method. A lower microbial diversity (p < 0.01) and a higher intersubject variability (p < 0.001) were found in patients as compared with reference individuals. At the time of malignancy diagnosis (i.e. before chemotherapy) patients that later developed mucositis showed a higher microbial diversity (p < 0.05) and a higher intersubject variability (p < 0.001) compared with those without mucositis. The change of bacterial composition during chemotherapy was more pronounced in patients who later developed mucositis than those without mucositis (p < 0.01). In conclusion, we found a higher microbial diversity at the time of malignancy diagnosis in patients who later develop oral mucositis and that these patients had a more significant modification of the bacterial community by chemotherapy before the occurrence of mucositis. These findings may possibly be of clinical importance in developing better strategies for personalized preventive management.

Extracting insights from the shape of complex data using topology.

This paper applies topological methods to study complex high dimensional data sets by extracting shapes (patterns) and obtaining insights about them. Our method combines the best features of existing standard methodologies such as principal component and cluster analyses to provide a geometric representation of complex data sets. Through this hybrid method, we often find subgroups in data sets that traditional methodologies fail to find. Our method also permits the analysis of individual data sets as well as the analysis of relationships between related data sets. We illustrate the use of our method by applying it to three very different kinds of data, namely gene expression from breast tumors, voting data from the United States House of Representatives and player performance data from the NBA, in each case finding stratifications of the data which are more refined than those produced by standard methods.

The potential of dual-energy computed tomography for quantitative decomposition of soft tissues to water, protein and lipid in brachytherapy.

Dosimetric accuracy of radiation treatment planning in brachytherapy depends on knowledge of tissue composition. It has been speculated that soft tissues can be decomposed to water, lipid and protein. The aim of our work is to evaluate the accuracy of such tissue decomposition. Selected abdominal soft tissues, whose average elemental compositions were taken from literature, were decomposed using dual energy computed tomography to water, lipid and protein via the three-material decomposition method. The quality of the decomposition was assessed using relative differences between (i) mass energy absorption and (ii) mass energy attenuation coefficients of the analyzed and approximated tissues. It was found that the relative differences were less than 2% for photon energies larger than 10 keV. The differences were notably smaller than the ones for water as the transport and dose scoring medium. The choice of the water, protein and lipid triplet resulted in negative elemental mass fractions for some analyzed tissues. As negative elemental mass fractions cannot be used in general purpose particle transport computer codes using the Monte Carlo method, other triplets should be used for the decomposition. These triplets may further improve the accuracy of the approximation as the differences were mainly caused by the lack of high-Z materials in the water, protein and lipid triplet.

A topological paradigm for hippocampal spatial map formation using persistent homology.

An animal's ability to navigate through space rests on its ability to create a mental map of its environment. The hippocampus is the brain region centrally responsible for such maps, and it has been assumed to encode geometric information (distances, angles). Given, however, that hippocampal output consists of patterns of spiking across many neurons, and downstream regions must be able to translate those patterns into accurate information about an animal's spatial environment, we hypothesized that 1) the temporal pattern of neuronal firing, particularly co-firing, is key to decoding spatial information, and 2) since co-firing implies spatial overlap of place fields, a map encoded by co-firing will be based on connectivity and adjacency, i.e., it will be a topological map. Here we test this topological hypothesis with a simple model of hippocampal activity, varying three parameters (firing rate, place field size, and number of neurons) in computer simulations of rat trajectories in three topologically and geometrically distinct test environments. Using a computational algorithm based on recently developed tools from Persistent Homology theory in the field of algebraic topology, we find that the patterns of neuronal co-firing can, in fact, convey topological information about the environment in a biologically realistic length of time. Furthermore, our simulations reveal a "learning region" that highlights the interplay between the parameters in combining to produce hippocampal states that are more or less adept at map formation. For example, within the learning region a lower number of neurons firing can be compensated by adjustments in firing rate or place field size, but beyond a certain point map formation begins to fail. We propose that this learning region provides a coherent theoretical lens through which to view conditions that impair spatial learning by altering place cell firing rates or spatial specificity.

From brain to bridge: masticatory function and dental implants.

Masticatory function is an important aspect of oral health, and oral rehabilitation should aim to maintain or restore adequate function. The present qualitative review is the joint effort of a group of clinicians and researchers with experiences ranging from basic and clinical oral neuroscience to management of patients with dental implants. The aim is to provide a short summary for the clinician of the many aspects related to masticatory function (including quality of life) and rehabilitation with dental implants. While there are many reviews on the tissue responses to dental implants and technical aspects, the functional aspects have received relatively little focus.

A phase I/II study of neoadjuvant chemotherapy with Pemetrexed (Alimta) in rectal cancer.

AIM: The aim was to assess the feasibility of preoperative chemotherapy and possible tumour response using Pemetrexed (Alimta) in rectal cancer. METHOD: The study was a prospective, non-randomized, single-centre phase I/II feasibility trial. 37 patients with resectable rectal cancer were recruited and given three 3-week cycles of preoperative Pemetrexed therapy. Tumour size and stage were assessed by MRI scans before and after chemotherapy. Treatment tolerability and response such as changes in tumour size and symptoms were assessed. RESULTS: All patients completed the chemotherapy. Whilst mild side effects were frequent (grade 1, 34/37), the risk of severe effects was limited (grade 3 or 4, 4/37). Overall, there was a significant reduction in tumour size (p < 0.001). By RECIST criteria, one patient had tumour progression, 23/36 had stable disease and 12 patients had a response of up to 65%. There was also a significant decrease in the number of pre-treatment symptoms (p < 0.018) including reduction of bleeding and diarrhoea/constipation. CONCLUSION: Preoperative (Neoadjuvant) treatment with Pemetrexed was feasible in studied patients. Serious side effects were limited and a radiological tumour response or stable disease was seen in a majority of patients.

Interictal and postictal performances on dichotic listening test in children with focal epilepsy.

Dichotic listening test (DL) is an important tool to disclose speech dominance in healthy subjects and in clinical cases. The aim of this study was to probe if focal epilepsy in children reveals a corresponding suppression of the ear reports contralateral to seizure onset site. Thus, 15 children and adolescents with clinically and electroencephalographically diagnosed focal epilepsy selected for left-hemisphere speech dominance without mental retardation were compared to matched controls according to age, gender, IQ and handedness. All children were assessed with DL for three times: Interictally (t(0)), postictally 5' (t(1)) and 1h (t(2)). At t(0), all groups revealed a right ear advantage (REA), indicating a left-hemisphere speech dominance. There was a continuous increase in right correct score (REC) over the trials for normal controls. Five minutes postictally, there was an abrupt decrease in REC with a sustained left ear correct score (LEC) for children with epilepsy, independent of which side suffered from seizures. This effect was maintained even after 1h. Thus, in children with left-hemisphere speech dominance the epileptic discharges caused a suppression of REC regardless of origin. The seizures may have a prolonged impact on attention and auditory perception for a considerable time after consciousness has been regained.

Phosphorous deficiency decreases nitrogenase activity but increases proton efflux in N2-fixing Medicago truncatula.

Effects of Sinorhizobium strain and P nutrition on N(2)-dependent growth, nitrogenase activity and proton efflux by nodulated roots were investigated in the model legume Medicago truncatula cultivar Jemalong grown in hydroaeroponic culture in symbioses with Sinorhizobium meliloti strains 102F51 and 2011. Sinorhizobium strain had strong effects on nitrogenase activity and N(2)-dependent growth, with S. meliloti 102F51 being the more efficient strain. Apparent and total nitrogenase activities, measured by hydrogen evolution in air and argon, respectively, were drastically reduced in plants supplied with 5 µmol P plant(-1) week(-1) as compared with 15 µmol P plant(-1) week(-1). There was a net proton efflux as soon as 2 weeks after inoculation and, in contrast to the effect of P nutrition on nitrogenase activity, P deficiency increased total and specific proton effluxes, irrespective of Sinorhizobium strain.