Beliefs about inevitable decline among home-living older adults at risk of malnutrition: a qualitative study.

BACKGROUND: Approximately 14% of free-living adults aged ≥65 years are at risk of malnutrition. Malnutrition screen and treat interventions in primary care are few, show mixed results, and the advice given is not always accepted and followed. We need to better understand the experiences and contexts of older adults when aiming to develop interventions that are engaging, optimally persuasive and relevant. METHODS: Using the Person-based Approach, we carried out 23 semi-structured interviews with purposively selected adults ≥65 years with chronic health or social conditions associated with malnutrition risk. Thematic analysis informed the development of key principles to guide planned intervention development. RESULTS: We found that individuals' beliefs about an inevitable decline in appetite and eating in older age compound the many and varied physical and physiological barriers that they experience. Also, we found that expectations of decline in appetite and physical ability may encourage resignation, reduce self-efficacy to overcome barriers, and reduce motivation to address weight loss and/or recognise it as an issue that needs to be addressed. Fear of loss of independence may also reduce the likelihood of asking general practitioners for advice. CONCLUSIONS: The key findings identified include a sense of resignation, multiple different barriers to eating and a need for independence, each underpinned by the expectation of a decline in older adulthood. Interventions need to address misperceptions about the inevitability of decline, highlight how and why diet recommendations are somewhat different from recommendations for the general population, and suggest easy ways to increase food intake that address common barriers.

Autosegmentation of the rectum on megavoltage image guidance scans.

Autosegmentation of image guidance (IG) scans is crucial for streamlining and optimising delivered dose calculation in radiotherapy. By accounting for interfraction motion, daily delivered dose can be accumulated and incorporated into automated systems for adaptive radiotherapy. Autosegmentation of IG scans is challenging due to poorer image quality than typical planning kilovoltage computed tomography (kVCT) systems, and the resulting reduction of soft tissue contrast in regions such as the pelvis makes organ boundaries less distinguishable. Current autosegmentation solutions generally involve propagation of planning contours to the IG scan by deformable image registration (DIR). Here, we present a novel approach for primary autosegmentation of the rectum on megavoltage IG scans acquired during prostate radiotherapy, based on the Chan-Vese algorithm. Pre-processing steps such as Hounsfield unit/intensity scaling, identifying search regions, dealing with air, and handling the prostate, are detailed. Post-processing features include identification of implausible contours (nominally those affected by muscle or air), 3D self-checking, smoothing, and interpolation. In cases where the algorithm struggles, the best estimate on a given slice may revert to the propagated kVCT rectal contour. Algorithm parameters were optimised systematically for a training cohort of 26 scans, and tested on a validation cohort of 30 scans, from 10 patients. Manual intervention was not required. Comparing Chan-Vese autocontours with contours manually segmented by an experienced clinical oncologist achieved a mean Dice Similarity Coefficient of 0.78 (SE < 0.011). This was comparable with DIR methods for kVCT and CBCT published in the literature. The autosegmentation system was developed within the VoxTox Research Programme for accumulation of delivered dose to the rectum in prostate radiotherapy, but may have applicability to further anatomical sites and imaging modalities.

Substrate texture affects female cricket walking response to male calling song.

Field crickets are extensively used as a model organism to study female phonotactic walking behaviour, i.e. their attraction to the male calling song. Laboratory-based phonotaxis experiments generally rely on arena or trackball-based settings; however, no attention has been paid to the effect of substrate texture on the response. Here, we tested phonotaxis in female Gryllus bimaculatus, walking on trackballs machined from methyl-methacrylate foam with different cell sizes. Surface height variations of the trackballs, due to the cellular composition of the material, were measured with profilometry and characterized as smooth, medium or rough, with roughness amplitudes of 7.3, 16 and 180 µm. Female phonotaxis was best on a rough and medium trackball surface, a smooth surface resulted in a significant lower phonotactic response. Claws of the cricket foot were crucial for effective walking. Females insert their claws into the surface pores to allow mechanical interlocking with the substrate texture and a high degree of attachment, which cannot be established on smooth surfaces. These findings provide insight to the biomechanical basis of insect walking and may inform behavioural studies that the surface texture on which walking insects are tested is crucial for the resulting behavioural response.

Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy.

To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is [Formula: see text], and the median DBC is ([Formula: see text]) mm. An intra-observer comparison for the same scans gives a median CI of [Formula: see text] and a DBC of ([Formula: see text]) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord.

Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy.

BACKGROUND AND PURPOSE: For the first time, delivered dose to the rectum has been calculated and accumulated throughout the course of prostate radiotherapy using megavoltage computed tomography (MVCT) image guidance scans. Dosimetric parameters were linked with toxicity to test the hypothesis that delivered dose is a stronger predictor of toxicity than planned dose. MATERIAL AND METHODS: Dose-surface maps (DSMs) of the rectal wall were automatically generated from daily MVCT scans for 109 patients within the VoxTox research programme. Accumulated-DSMs, representing total delivered dose, and planned-DSMs, from planning CT data, were parametrised using Equivalent Uniform Dose (EUD) and 'DSM dose-width', the lateral dimension of an ellipse fitted to a discrete isodose cluster. Associations with 6 toxicity endpoints were assessed using receiver operator characteristic curve analysis. RESULTS: For rectal bleeding, the area under the curve (AUC) was greater for accumulated dose than planned dose for DSM dose-widths up to 70Gy. Accumulated 65Gy DSM dose-width produced the strongest spatial correlation (AUC 0.664), while accumulated EUD generated the largest AUC overall (0.682). For proctitis, accumulated EUD was the only reportable predictor (AUC 0.673). Accumulated EUD was systematically lower than planned EUD. CONCLUSIONS: Dosimetric parameters extracted from accumulated DSMs have demonstrated stronger correlations with rectal bleeding and proctitis, than planned DSMs.

Treatment of cranial cruciate ligament rupture in the feline stifle. Biomechanical comparison of a standard fabella-tibial suture and lateral sutures placed between quasi-isometric points.

OBJECTIVE: To determine whether a lateral suture placed with bone anchors between quasi-isometric points in a cat is superior to a standard fabella-tibial suture for the stabilization of cranial cruciate ligament (CrCL) rupture compared to an intact stifle joint. STUDY DESIGN: Biomechanical cadaveric study. METHODS: Six stifle joints with intact cruciate ligaments from three skeletally mature cats were placed in a loading mounting set and tested with axial loads of 20N and 60N at three different joint angles (75°,130° and 160°). The procedure was repeated with a transected CrCL; a stabilized stifle joint after a combination of three lateral suture techniques (fabella-tibial suture technique [SFT]; femoro-tibial suture technique 1 [FTS-1] and femoro-tibial suture technique 2 [FTS-2]). Radiographic examination of the relative position of the tibia to the fixed femur was compared. RESULTS: Stabilization of the stifle joint with lateral sutures had comparable stability to the intact specimens in the cranio-caudal direction (p = 0.2) but not in the proximo-distal direction for the SFT (p = 0.04) and FTS-2 technique (p = 0.03). There was no significant difference between the three stabilization techniques (p >0.05). CLINICAL SIGNIFICANCE: Lateral sutures placed with bone anchors at quasi-isometric points performed better than SFT and FTS-2 in stabilizing the feline stifle after CrCL rupture in the proximo-distal plane. Biomechanical stability in the cranio-caudal plane after placement of a lateral suture across the feline stifle was similar to the intact CrCL.

Random variation in rectal position during radiotherapy for prostate cancer is two to three times greater than that predicted from prostate motion.

OBJECTIVE: Radiotherapy for prostate cancer does not explicitly take into account daily variation in the position of the rectum. It is important to accurately assess accumulated dose (DA) to the rectum in order to understand the relationship between dose and toxicity. The primary objective of this work was to quantify systematic (Σ) and random (σ) variation in the position of the rectum during a course of prostate radiotherapy. METHODS: The rectum was manually outlined on the kilo-voltage planning scan and 37 daily mega-voltage image guidance scans for 10 participants recruited to the VoxTox study. The femoral heads were used to produce a fixed point to which all rectal contours were referenced. RESULTS: Σ [standard deviation (SD) of means] between planning and treatment was 4.2 mm in the anteroposterior (AP) direction and 1.3 mm left-right (LR). σ (root mean square of SDs) was 5.2 mm AP and 2.7 mm LR. Superior-inferior variation was less than one slice above and below the planning position. CONCLUSION: Our results for Σ are in line with published data for prostate motion. σ, however, was approximately twice as great as that seen for prostate motion. This suggests that DA may differ from planned dose in some patients treated with radiotherapy for prostate cancer. ADVANCES IN KNOWLEDGE: This work is the first to use daily imaging to quantify Σ and σ of the rectum in prostate cancer. σ was found to be greater than published data, providing strong rationale for further investigation of individual DA.

Barriers and facilitators to screening for malnutrition by community nurses: a qualitative study.

BACKGROUND: A substantial proportion of individuals who live in community settings in the UK experience malnutrition. Routine screening for malnutrition by healthcare practitioners has been recommended in many regions. The present study aimed to understand community nurses' perceptions of barriers and facilitators to undertaking nutritional screening. METHODS: A qualitative study was undertaken with a purposive sample of community nurses working in one UK healthcare organisation. Semi-structured interviews were used to elicit perceptions of barriers and facilitators. Interviews were digitally recorded, anonymised and transcribed. Initial codes were assigned for salient constructs identified in the transcripts, refined by grouping, and a thematic list was developed. RESULTS: Twenty district nurses and community matrons were interviewed at which time saturation of the data was achieved. Six themes emerged: supportive organisational culture, time and resource to screen and intervene, ease and acceptability of the screening tool, professional judgement as good as screening, the need for training and sharing good practice, and enhancing communication between care settings. CONCLUSIONS: The findings of the present study suggest that screening is more likely to be completed where an organisation is perceived to have a clear expectation that it is undertaken and also demonstrates this through training and availability of resources. The need for a process or tool that nurses find easy to use and relevant to their practice area was highlighted. Further research should examine the effect of the use of a nutritional screening tool by community nurses on nutritional care planning and intervention.

Feline talocrural luxation: a cadaveric study of repair using ligament prostheses.

Currently recommended surgical techniques to treat severe biaxial feline talocrural soft-tissue injuries commonly lead to unsatisfactory outcome. Data relating to canine talocrural stabilisation may not be useful in cats due to major differences in tarsal anatomy between the species. This experimental biomechanical cadaveric study used specimens (n = 10) prepared from the distal pelvic limbs of five adult cats. The aim was to design a technique for treating talocrural luxation using suture prostheses and bone tunnels, and to investigate its suitability for use in clinical cases. Four prosthetic ligaments were placed through a series of five 1.5 mm bone tunnels. Two prostheses, the caudoproximal pair, were taut in talocrural flexion and two prostheses, the craniodistal pair, were taut in extension. The intact specimens had their range-of-motion (ROM) and stability tested, after which they were transected at the talocrural joint (simulated luxation) and repaired using the technique described. The ROM and stability of the repaired specimens were tested and compared to the intact specimens. The repaired specimens had comparable stability to the intact specimens, although the ROM was different (p <0.05) in six of 16 positions (p <0.003125). These corresponded to the positions where the lateral prostheses were taut. The repair technique described may be useful in the treatment of talocrural luxation, as it is low-profile in an area of limited soft-tissue cover, allows anatomic reduction, restores normal talocrural joint stability and near-normal tarsal ROM.

The tension band principle and angular testing of extensor tendon repairs.

Extensor tendons in the finger are flat and not amenable to repair by core and epitendinous sutures. Mattress sutures and Kessler repairs without epitendinous stitching are often used for extensor tendon divisions in the fingers. Except when in full extension, the finger presents a series of curved surfaces (at each joint) to the tendon. It was hypothesized that extensor tendons are subject to the 'tension band' principle and that they might be amenable to repair by dorsal-only epitendinous sutures. A Silfverskiöld dorsal-only repair was compared with mattress and Kessler repairs in vitro on a curvilinear testing apparatus. The epitendinous technique was found to be significantly more resistant to gapping and rupture, as well as more resistant to deformation (i.e. stiffer) than the conventional techniques.

The response of the tandem pore potassium channel TASK-3 (K(2P)9.1) to voltage: gating at the cytoplasmic mouth.

Although the tandem pore potassium channel TASK-3 is thought to open and shut at its selectivity filter in response to changes of extracellular pH, it is currently unknown whether the channel also shows gating at its inner, cytoplasmic mouth through movements of membrane helices M2 and M4. We used two electrode voltage clamp and single channel recording to show that TASK-3 responds to voltage in a way that reveals such gating. In wild-type channels, P(open) was very low at negative voltages, but increased with depolarisation. The effect of voltage was relatively weak and the gating charge small, 0.17. Mutants A237T (in M4) and N133A (in M2) increased P(open) at a given voltage, increasing mean open time and the number of openings per burst. In addition, the relationship between P(open) and voltage was shifted to less positive voltages. Mutation of putative hinge glycines (G117A, G231A), residues that are conserved throughout the tandem pore channel family, reduced P(open) at a given voltage, shifting the relationship with voltage to a more positive potential range. None of these mutants substantially affected the response of the channel to extracellular acidification. We have used the results from single channel recording to develop a simple kinetic model to show how gating occurs through two classes of conformation change, with two routes out of the open state, as expected if gating occurs both at the selectivity filter and at its cytoplasmic mouth.

Experimental measurement of the mechanical properties of carotid atherothrombotic plaque fibrous cap.

Eleven carotid atherothrombotic plaque samples were harvested from patients. Three samples that were highly calcified were discarded, while eight yielded results. The elastic properties of the material were estimated by fitting the measured indentation response to finite element simulations. The methodology was refined and its accuracy quantified using a synthetic rubber. The neo-Hookean form of the material model gave a good fit to the measured response of the tissue. The inferred shear modulus mu was found to be in the range 7-100 kPa, with a median value of 11 kPa. A review of published materials data showed a wide range of material properties for human atherothrombotic tissue. The effects of anisotropy and time dependency in these published results were highlighted. The present measurements were comparable to the static radial compression tests of Lee et al, 1991 [Structure-dependent dynamic behaviour of fibrous caps from human atherosclerotic plaques. Circulation 83, 1764-1770].

A biomechanical comparison of six different double loop configurations for use in the lateral fabella suture technique.

Six different double loop configurations which could be applied to the lateral fabella suture (LFS) technique were subjected to in vitro mechanical testing. Three double loop, single strand and three double loop, double strand configurations were tested. The strongest configuration, with a significantly higher mean ultimate load and load at yield, was the interlocking loop configuration. This is a novel configuration which has not previously been reported. The three double loop, single strand configurations all had higher mean ultimate loads than the double loop, double strand configurations. The double strand group with uneven loop length performed very poorly, with significantly lower mean stiffness and ultimate load than all of the single strand groups. This group also developed unacceptably high levels of elongation during high level cyclic loading.

Characterization of inhibitors and substrates of Anopheles gambiae CYP6Z2.

Three CYP6Z genes are linked to a major pyrethroid resistance locus in the mosquito Anopheles gambiae. We have expressed CYP6Z2 in Escherichia coli and produced a structural model in order to examine its role in detoxification. E. coli membranes co-expressing CYP6Z2 and An. gambiae P450 reductase (AgCPR) catalysed the dealkylation of benzyloxyresorufin with kinetic parameters K(m) = 0.13 microM; K(cat) = 1.5 min(-1). The IC(50) values of a wide range of compounds were measured. Pyrethroids cypermethrin and permethrin produced low IC(50) values, but were not metabolized. Plant flavanoids were the most potent inhibitors. Several compounds were shown to be substrates, suggesting that CYP6Z2 has broad substrate specificity and plays an important chemo-protective role during the herbivorous phase of the life-cycle.

Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6-drug interactions.

The cytochromes P450 (CYPs) comprise a vast superfamily of enzymes found in virtually all life forms. In mammals, xenobiotic metabolizing CYPs provide crucial protection from the effects of exposure to a wide variety of chemicals, including environmental toxins and therapeutic drugs. Ideally, the information on the possible metabolism by CYPs required during drug development would be obtained from crystal structures of all the CYPs of interest. For some years only crystal structures of distantly related bacterial CYPs were available and homology modelling techniques were used to bridge the gap and produce structural models of human CYPs, and thereby obtain useful functional information. A significant step forward in the reliability of these models came seven years ago with the first crystal structure of a mammalian CYP, rabbit CYP2C5, followed by the structures of six human enzymes, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6 and CYP3A4, and a second rabbit enzyme, CYP2B4. In this review we describe as a case study the evolution of a CYP2D6 model, leading to the validation of the model as an in silico tool for predicting binding and metabolism. This work has led directly to the successful design of CYP2D6 mutants with novel activity-including creating a testosterone hydroxylase, converting quinidine from inhibitor to substrate, creating a diclofenac hydroxylase and creating a dextromethorphan O-demethylase. Our modelling-derived hypothesis-driven integrated interdisciplinary studies have given key insight into the molecular determinants of CYP2D6 and other important drug metabolizing enzymes.

The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1: contributions of the pore domains.

We have investigated the contribution to ionic selectivity of residues in the selectivity filter and pore helices of the P1 and P2 domains in the acid sensitive potassium channel TASK-1. We used site directed mutagenesis and electrophysiological studies, assisted by structural models built through computational methods. We have measured selectivity in channels expressed in Xenopus oocytes, using voltage clamp to measure shifts in reversal potential and current amplitudes when Rb+ or Na+ replaced extracellular K+. Both P1 and P2 contribute to selectivity, and most mutations, including mutation of residues in the triplets GYG and GFG in P1 and P2, made channels non-selective. We interpret the effects of these--and of other mutations--in terms of the way the pore is likely to be stabilised structurally. We show also that residues in the outer pore mouth contribute to selectivity in TASK-1. Mutations resulting in loss of selectivity (e.g. I94S, G95A) were associated with slowing of the response of channels to depolarisation. More important physiologically, pH sensitivity is also lost or altered by such mutations. Mutations that retained selectivity (e.g. I94L, I94V) also retained their response to acidification. It is likely that responses both to voltage and pH changes involve gating at the selectivity filter.

Flavoenzyme catalysed oxidation of amines: roles for flavin and protein-based radicals.

Amines are a carbon source for the growth of a number of bacterial species and they also play key roles in neurotransmission, cell growth and differentiation, and neoplastic cell proliferation. Enzymes have evolved to catalyse these reactions and these oxidoreductases can be grouped into the flavoprotein and quinoprotein families. The mechanism of amine oxidation catalysed by the quinoprotein amine oxidases is understood reasonably well and occurs through the formation of enzyme-substrate covalent adducts with TPQ (topaquinone), TTQ (tryptophan tryptophylquinone), CTQ (cysteine tryptophylquinone) and LTQ (lysine tyrosyl quinone) redox centres. Oxidation of amines by flavoenzymes is less well understood. The role of protein-based radicals and flavin semiquinone radicals in the oxidation of amines is discussed.

Biodiversity of cytochrome P450 redox systems.

P450s (cytochrome P450 mono-oxygenases) are a superfamily of haem-containing mono-oxygenase enzymes that participate in a wide range of biochemical pathways in different organisms from all of the domains of life. To facilitate their activity, P450s require sequential delivery of two electrons passed from one or more redox partner enzymes. Although the P450 enzymes themselves show remarkable similarity in overall structure, it is increasingly apparent that there is enormous diversity in the redox partner systems that drive the P450 enzymes. This paper examines some of the recent advances in our understanding of the biodiversity of the P450 redox apparatus, with a particular emphasis on the redox systems in the pathogen Mycobacterium tuberculosis.