Since its discovery, the hemochromatosis protein HFE has been primarily defined by its role in iron metabolism and homeostasis, and its involvement in the genetic disease termed hereditary hemochromatosis (HH). While HH patients are typically afflicted by dysregulated iron levels, many are also affected by several immune defects and increased incidence of autoimmune diseases that have thereby implicated HFE in the immune response. Growing evidence has supported an immunological role for HFE with recent studies describing HFE specifically as it relates to MHC I antigen presentation.Here, we present a comprehensive overview of the relationship between iron metabolism, HFE, and the immune system to better understand the origin and cause of immune defects in HH patients. We further describe the role of HFE in MHC I antigen presentation and its potential to impair autoimmune responses in homeostatic conditions, a mechanism which may be exploited by tumors to evade immune surveillance.Overall, this increased understanding of the role of HFE in the immune response sets the stage for better treatment and management of HH and other iron‐related diseases, as well as of the immune defects related to this condition. The human body employs multiple mechanisms in order to maintain metabolic homeostasis. To maintain this balance, the immune system is of paramount importance, providing protection against pathogens such as bacteria, fungi, parasites, and viruses, in addition to guarding against malignant transformations and cancer development Links have been established between metabolism and immunity with discoveries revealing the impact of glycolysis on T cell maturation and activation HFE was identified in 1996 as the gene responsible for HH Initial studies on the function of HFE revealed that it is involved in modulating iron uptake by the transferrin receptor 1 (TfR1) C282Y is most common among Caucasians, with a relatively high prevalence of 1 in 10 within this population Hereditary forms of hemochromatosis arising from hepcidin deficiency are primarily related to the C282Y mutation in HFE, with rare forms involving mutations in HJV and hepcidin While there are no doubts that HFE plays an important role in iron metabolism, its remarkable similarity to the structure of MHC I molecules raises questions on HFE involvement in the immune response, specifically through antigen presentation.MHC molecules are host‐cell glycoproteins at the cell surface that are specialized in presenting antigens to T lymphocytes. Antigen presentation is part of an active monitoring mechanism to detect harmful or invading agents, and involves generating peptides (antigens) from endogenous or exogenous proteins for display by MHC I or MHC II molecules, respectively. MHC I is present in all nucleated cells in the body, whereas MHC II tends to be limited to professional antigen presenting cells (pAPC) such as macrophages, dendritic cells (DC), and B lymphocytes. The display of MHC‐bound peptides to T lymphocytes initiates an immune response for the effective elimination of infected and damaged cells while avoiding autoimmunity by discriminating between “foreign” and “self” antigens. Therefore, a perfect balance must be achieved between the specific and promiscuous binding of antigens that can be presented on the same MHC molecules Classical MHC I molecules display peptides derived from antigens within the cell, including those that are from “self,” pathogen‐associated, or cancer‐associated proteins. Prior to their presentation, these proteins are digested in the cytosol and are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), which forms a peptide‐loading complex (PLC) with nascent MHC I molecules stabilized by the chaperones tapasin, calreticulin, and ERp57 Fig.  29. The + T lymphocytes, and lysis of infected cells through production of granzyme and perforin Antigen presentation is without consequence if the presented antigens are not recognized by the T cell receptor (TCR) on T lymphocytes In response to inflammatory stimuli, the immune system tightly regulates MHC I antigen processing to maintain tolerance to self‐antigens and tend to the immediate needs of the host. The promoter region of MHC I genes are activated by multiple pathways that enable dynamic expression under such different conditions Pseudomonas aeruginosa to induce TAP degradation, and intracellular growth by Salmonella spp. is reduced to minimize antigenic content in the host cell, among others MHC I molecules are particularly specialized to display peptides of invading or intracellular pathogens to CTLs and initiate activation events that lead to the elimination of infected cells. For survival, pathogens have developed strategies to interfere with the antigen presentation pathway and escape immune surveillance at each stage of this process Salmonella typhi, Mycobacterium tuberculosis, and the human CMV Classical MHC I molecules are associated with cellular adaptive immunity. However, non‐classical MHC I molecules, termed MHC Ib, contribute to alternate forms of immune surveillance and immune suppression that support both the innate and adaptive immune response. Although evolutionarily and structurally related, MHC Ib molecules are more limited in their polymorphisms and patterns of expression compared to their classical MHC I counterparts. MHC Ib molecules also include proteins encoded outside the MHC gene locus, possess functions extending beyond peptide presentation, and interact with receptors across both the innate and adaptive immune systems HFE is also a non‐classical MHC Ib molecule, but does not appear to have any antigen‐binding capabilities HFE was originally named HLA‐H due to its homology with the MHC I structure, characterized by a heavy chain comprised of three alpha domains and a transmembrane (TM) domain C282Y and HFEH63DC282Y prevents formation of a disulfide bond located in the α3 domain of HFE, critical for β2‐m binding and protein stability C282Y prevents extracellular expression of HFE and subsequent interactions with the TfR1, resulting in an increase in cellular iron uptake without HFE interference at the cell surface Many HFE mutants have been exploited to better characterize the interaction of HFE and TfR1. The most prevalent mutations identified within patients and associated with HH are HFEH63D can still associate with TfR1, however, the substitution of a histidine (H) for an aspartic acid (D) modulates TfR1 affinity for Tf. Whereas wild‐type HFE reduces the affinity of TfR1 for Tf to downregulate iron uptake, HFEH63D was shown to also decrease the TfR1‐Tf interaction though to a lesser degree The H63D mutation is situated in the α1 domain of HFE and does not affect binding with β2‐m, thereby leaving HFE surface expression unaltered. HFEWT in the liver for iron metabolism WT and implications in responding to iron disorders such as HH HFE is expressed ubiquitously but its expression levels vary greatly from one tissue to another + T cells through antigen‐specific MHC I molecules, or by NK cells detecting absent or decreased expression of MHC I. Importantly, HFE is not recognized by NK cells Non‐classical MHC I (class Ib) molecules such as HLA‐E, ‐F, and ‐G have been shown to bind to NK cells with effects on immunoregulation, autoimmunity, and immune tolerance during pregnancy. NK cells are generally involved in the innate immune response, as they do not require antigen‐specific recognition to kill infected cells NKT cells are a subset of T lymphocytes that express surface receptors that are characteristic of both T and NK cell lineages Recently, a study comparing HH patients and control individuals reported reduced numbers of circulating iNKT in HH patients + T cell pool have been associated with HH. Iron can directly affect the phenotype of immune cells, and was shown in vitro to inhibit the surface expression of adhesion molecule CD2 and co‐receptor CD4 on T lymphocytes + T cells, affecting CD4/CD8 ratios + T cell numbers may affect intestinal iron absorption levels. The decrease in CD8+ T lymphocytes in HH patients appears to be related to defects in the subpopulation that cannot differentiate into CD8+ effector memory T cells The relationship between HH and modulation of the immune response is strongly suggested by the abundance of immune defects identified in HH patients + T cell subsets in HH, such as regulatory CD8+CD28− T cells, which coincided with a decrease in CD8+CD28+ T cells and diminished cytotoxic activity of CTLs + T cell subset Tc2, and may encourage Th2 polarization in certain contexts Alternatively, other studies have documented an increased presence of some CD8+ T lymphocytes and HH with associated iron overload. A potential immunological function for HFE has been further implicated with the discovery of HFE and its striking homology with MHC I , a mechanism that impacts intracellular trafficking, and gives rise to MHC I anomalies in HFEC282Y cells + T cells, particularly those expressing the variable AV6.1 and AV6.6 gene segments + T lymphocyte activation. One study evaluated how the presence of wild‐type and mutated HFE molecules affected the ability of MHC I molecules, specifically HLA‐A2, to present selected antigens and subsequently activate CD8+ T lymphocytes C282Y, inhibited the secretion of T cell cytokines and the expression of lymphocyte activation markers, demonstrating the functional impact of HFE on CD8+ T lymphocytes. The inhibition of CD8+ T lymphocyte activation involved the α1–2 domains of wild‐type HFE and was independent of MHC I expression level, β2‐m competition, HFE‐TfR1 interaction, or epitope origin and affinity + T lymphocyte reactivity, which could modulate antigen immunogenicity.The findings of all these studies present a strong and undeniable link between the immunity involving CD8C I Fig. A and B. C I Fig. C. Periph+ T lymphocyte activation was demonstrated in another study revealing that HFE has an impact on the expression of genes associated with the differentiation, maturation and activation of CD8+ T lymphocytes, both in HH patients and in Hfe‐deficient mice + T memory cells, thereby affecting the homeostatic equilibrium of these cells. The authors proposed that the “low CD8 phenotype” in HH may be the result of a homeostatic equilibrium of cells constantly triggered to activate and differentiate into more mature effector cells Further support for an HFE role as a negative regulator of CD8+ lymphocyte activation are related to the immune response during infections, cancer immune surveillance, and autoimmunity. A summary of the impact of HFE expression on iron metabolism and MHC I antigen presentation is presented in Table The most obvious implications of HFE as a negative regulator/inhibitor of MHC I antigen presentation and CD8C282Y enhances immune responses, then this would likely impact resistance to infections in HH patients. Because most pathogens during infection depend on iron to replicate and survive Vibrius vulnificus and Yersinia enterocolitica, Gram‐negative bacteria that thrive in excess iron V. vulnificus infections in HH patients develop into gastroenteritis from raw shellfish, wound infections, and septicaemia; however, it is not known if there is a direct association between mutated HFEC282Y and a higher risk for Vibrius infections V. vulnificus in hepcidin‐deficient mice V. vulnificus. When treated with hepcidin agonists, susceptible mice were rescued from death with the induction of hypoferremia (low iron). This is consistent with the described role for hepcidin in innate immunity which recognizes hepcidin as a defensin‐like antimicrobial peptide, responding to iron overload and inflammation, binding to ferroportin, and causing downstream effects that restrict levels of iron for invading pathogens If mutated HFES. typhi, M. tuberculosis, and Chlamydia pneumoniae, which depend on high intracellular iron concentrations to multiply in their host cell C282Y was also shown to increase MHC I antigen presentation compared to HFEWTC282Y mutation in European populations suggests an evolutionary selection driven by centuries of past pandemics and dietary changes that reflect low availability of iron‐rich foods In general, the impaired iron retention in macrophages from HFE mutation results in an iron deficiency that can attenuate the survival of intracellular pathogens such as C282Y may favor the appearance of autoimmunity. Various reports have described autoimmune conditions in association with hemochromatosis. In particular a higher prevalence of the HFEC282Y mutation was observed among cases of multiple sclerosis (MS) and was present among MS patients that had an accelerated onset of the disease and more severe MS symptoms C282Y concluded that autoimmune conditions were common among individuals with hemochromatosis C282Y mutation could increase the self‐reactivity of CD8+ T cells that cross the blood‐brain barrier, via increased MHC I antigenic presentation. The HFEC282Y mutation may result in an increased presentation of auto‐antigens related to MS beyond a recognition threshold causing the onset and progression of the disease, unlike HFEWT which could inhibit presentation and maintain immunosuppression From a different perspective, enhanced immune responses by mutated HFEC282Y or HFEH63D within tumors that would enhance cancer progression C282Y and HFEH63D in tumors, with positive correlations between the presence of the HFEC282Y mutation (heterozygous and homozygous) and the development of cancers such as breast, ovarian, colorectal, and hepatocellular carcinoma + T cells, it is plausible that HFE may impact the immune surveillance of tumors WT rather than HFEC282Y, was shown to inhibit MHC I presentation and T cell activation The implications of HFE mutations in cancer development and progression have been extensively investigated since iron is essential for cell proliferation and is in higher demand in cancer metabolism. To date, no study has established a selective mutation from wild‐type to HFE+ T cell activation, revealing an immunological role as a negative regulator of MHC I antigen presentation. HFE association with T cells was also previously highlighted with animal studies that demonstrated that iron overload is more prominent in RAG1 mice deficient in lymphocytes and in HFE‐deficient mice on a RAG1 background C282Y has been associated with the UPR, a cellular stress response affecting the MHC I pathway, which may provide new clues that link UPR signaling pathways and HH pathophysiology Although HFE cannot present antigens, it actively participates in the MHC I pathway and CD8+ T cells leading to tumor lysis and eradication. These studies may highlight possible mechanisms that involve HFE in the anti‐tumor immune response. In addition, further studies in the expression of HFE variants in different tissues, such as sHFE may further elucidate specific roles of HFE. The α1‐2 domains of HFEWT are responsible for the inhibition of MHC I presentation The expression of HFE appears to vary based on immune mediators present in the immediate inflammatory microenvironment + T cells, thereby preventing immune‐derived damage to a central organ of the body. Alternatively, the low levels of HFE detected in the brain The immunosuppressive activity of HFE on MHC I antigen presentation may highlight other roles as a mediator in maintaining homeostasis in human tissues. In particular, certain organs have an immune privileged status that is maintained by immune‐suppressive mechanisms and the presence of physical barriers to limit immune infiltration. Some studies suggest that the liver is one of these immune privileged bodies + T cell reactivity, and animal studies have highlighted how iron overload is more pronounced in lymphocyte‐deficient mice. In addition, HFEWT has now been shown to inhibit antigen presentation via the MHC I pathway with immunosuppressive effects on CD8 T cells. HFE expression levels may be dependent upon the presence of immune mediators or an inflammatory microenvironment capable of regulating MHC I presentation and of driving the immune response for clearance. While the direct impact of HFE mutations is evident for iron overload, the direct immunological role of these mutations or of HFE isoforms, such as sHFE, is less clear, particularly in the context of immune defects observed in HH patients. HFE mutations, the resulting iron imbalance, or both events may predispose HH patients or modify their response in the development of cancer, autoimmune diseases, and adaptive immunity to pathogens. Further investigation is necessary to characterize the dual roles of HFE and how both the immune system and iron metabolism regulate each other.HFE has been described primarily for its role in iron metabolism, however, defining an immunological role for HFE has been of great interest since discovering its remarkable structural homology with MHC I molecules. Recent studies show that, similar to other non‐classical MHC Ib molecules, HFE demonstrates immune activities that bridge innate and adaptive immunity. The immunological abnormalities of HH patients have drawn attention to HFE involvement in CD8None declared.


The use of non‐aqueous organic media is becoming increasingly important in many biotechnological applications in order to achieve process intensification. Such media can be used, for example, to directly extract poorly water‐soluble toxic products from fermentations. Likewise many biological reactions require the supply of oxygen, most normally from air. However, reliable online measurements of oxygen concentration in organic solvents (and hence oxygen transfer rates from air to the solvent) has to date proven impossible due to limitations in the current analytical methods.THF, isooctane, DMF, heptane and hexane . Subsequently, the oxygen transfer rates from air into these organic solvents were measured.For the first time, online oxygen measurements in non‐aqueous media using a novel optical sensor are demonstrated. The sensor was used to measure oxygen concentration in various organic solvents including toluene, Journal of Chemical Technology & Biotechnology published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry.The measurement of oxygen transfer rates from air into organic solvents using the dynamic method was established using the solvent resistant optical sensor. The feasibility of online oxygen measurements in organic solvents has also been demonstrated, paving the way for new opportunities in process control. © 2015 The Authors.  LaKoxygen mass transfer coefficient2]*[Osaturation concentration of oxygen2][Oconcentration of oxygen at a given time2*pOsaturation partial pressure of oxygen2pOpartial pressure of oxygen at a given timeHHenry's Law constantOxygen transfer is important in many bioprocesses employed at industrial scale. In aerobic fermentation and biocatalysis using growing cells, oxygen is used both for cell growth and maintenance. Likewise in biocatalysis, using resting cells or isolated enzymes for chemical synthesis, oxygen is used as a substrate in many reactions such as those catalysed by oxidases2 L−1 water .−1 oxygen. The higher oxygen solubility in organic solvents gives a higher concentration driving force for mass transfer, resulting in improved transfer rates. On this premise we reasoned that the application of a sensor suitable for measurement of oxygen concentration in organic solvents would be useful.While most bioprocesses are carried out in an aqueous solution, there is increasing interest in the use of non‐aqueous media to partially, or completely, replace water.Indeed, historically the determination of oxygen solubility in organic solvents has proven challenging. Methods reported include titration, use of manometers, photochemical methods, electron spin resonance and chromatography.All solvents, unless specified, were purchased in analytical grade from Sigma Aldrich  and used as purchased. The solvent‐resistant oxygen sensors (model OXSOLV) and the FirestingO2 were obtained from PyroScience .2pO) were obtained using two mass flow controllers (Read‐Ysmart series) from Vögtlin instruments (www.voegtlin.com). Compressed air and pure nitrogen were used as calibration gases. The mixtures were controlled with an oxygen microsensor (model OXR230‐CL4) from PyroScience. The calibration gas was passed through a glass trap and subsequently a glass measurement cell (maintained at 25 °C in a water bath). In turn the glass trap and the measurement cell were filled with the organic solvents to be evaluated.Gas mixtures of defined oxygen partial pressure  on a single drive shaft, and two baffles (of 1 cm width). Both the height of the impellers and the agitation speed were adjustable.A 2‐point calibration was made for the oxygen sensors by exposing them to air (for 100% DO) and 1% sodium sulphite (for 0% DO). The calibration for the zero reading was carried out with sodium sulphite since it was a fast and an easy‐to‐use calibration method.Lak measurements were made for oxygen transferring from air to heptane, MTBE, isooctane and cyclohexane respectively, using the well‐established dynamic gassing out method.50 mL of a given organic solvent was placed in the stirred tank reactor (maintained at 37 °C in a water bath) and the stirring speed was set to 80 rpm for all solvents ensuring that the solvent was mixed without disturbing the surface. The low stirring speed ensured that there was no splashing and thus a fixed gas–liquid interfacial area was made available for oxygen transfer. The headspace was flushed with nitrogen until the oxygen concentration in the aqueous phase stabilized (zero reading). Subsequently, the nitrogen flow was stopped and the reactor left open to enable to fill the headspace. Oxygen then transferred from the headspace to a given organic solvent until the two were equilibrated. The increase in oxygen concentration in the respective organic solvent was measured using two oxygen sensors (one attached to each baffle) enabling duplicate measurements. For calculation of the specific interfacial area (a) available for oxygen transfer, the volume of the solvents was considered to be 50 mL. Exceptionally in the case of MTBE, the volume used was 40 mL on account of evaporation losses during degassing, resulting in a higher specific interfacial area.In the following section, we report the measurement of oxygen concentration and transfer rate of oxygen from air to neat organic solvents. To that end, the oxygen sensor was first characterized in different solvents followed by use them in organic solvents with the aim of measuring oxygen transfer rates.90) of 4 s, fast enough for the measurements required in the dynamic method. Figure Initially, the oxygen sensor was tested in representative organic solvents, covering a wide range of different polarities. The active sensor coating is composed of a Teflon‐like hydrophobic polymer, which makes it resistant to a range of non‐aqueous solvents. The sensor was exposed to the organic solvents for 1 h. The sensors showed a response time  and which also met environmental guidelines, using the ACS GCI solvent selection guide.Oxygen transfer rates from the headspace to the organic phase were measured by the well‐established dynamic method.Lak measurements have a fast response in order to avoid any errors due to artefacts as a result of the measurement itself.When the nitrogen sweeps out the air from the headspace, the oxygen concentration becomes zero. When headspace aeration follows, the oxygen concentration rises in the system until it reaches the saturation concentration :According to Henry's law, the concentration of oxygen in solution in equilibrium with the gas, [pO2) and saturation partial pressure (pO2*) gives:Re‐writing Equation (2) in terms of partial pressure (Solving Equation (4) gives:Lak for each solvent can be obtained from the plot of ln (pO2*–pO2) as a function of time. Partial pressures were measured using the sensors  is required, the solvent sensors could be placed in each of the phases (aqueous and organic) and oxygen concentrations measured over time. The result obtained would in turn indicate the mass transfer rates from gas to organic phase and subsequently organic phase to aqueous phase.Oxygen transfer rates from air to neat organic solvents were determined with a solvent‐resistant optical sensor. The study demonstrates for the first time the feasibility of online measurements of oxygen in organic solvents, which was previously limited by unstable sensors. The sensor therefore presents new possibilities in process control of intensified fermentation and biocatalytic processes where changes in oxygen concentrations occur in the presence of organic solvents.The authors declare that there are no conflicts of interest.


Fluence optimization and beam aperture calculation using the new technique offers a ten‐fold reduction in planning time and significantly reduces the likelihood of user error during the planning process. In conclusion, a clinically viable aperture modulated translating bed TBI technique that employs dynamically shaped MLC‐defined beam apertures based on radiological depth calculations, has been developed.We have previously demonstrated the use of Eclipse fluence optimization to define aperture sizes for a novel aperture modulated translating bed total body irradiation (TBI) technique. The purposes of the present study were to identify, characterize, and correct for sources of error inherent in our previous fluence optimization technique, and to develop a clinically viable fluence optimization module for the translating bed TBI technique. Aperture modulated TBI is delivered by translating the patient at constant speed on a custom bed under a modulated radiation beam. The patient is then turned from supine to prone and the process repeated, resulting in an AP‐PA treatment. Radiological depths were calculated along divergent ray lines through individual CT slices of a RANDO phantom. Beam apertures, defined using a dynamic multileaf collimator (DMLC), were generated using calculated radiological depths and calibration factors that relate fluence to aperture size in a dynamic environment. These apertures were defined every 9 mm along the phantom superior‐inferior axis. The calculated beam apertures were further modified to account for scatter within the patient. For dose calculation purposes the individual MLC files were imported into Eclipse. For treatment delivery, dynamic MLC files for both AP and PA beams were generated and delivered dynamically. Dose homogeneity in the head and neck region of the RANDO phantom was within PACS numbers: 87.55.‐x, 87.55.D‐ A number of linac‐based TBI techniques have been developed to improve dose uniformity. One such method is to compensate for external contour variation using bolus around the patient or using copper blocks of variable thicknesses mounted to the head of the linac. Some investigators have used compensation based on water columns of different heights. Physical compensators, however, are labor intensive to fabricate, and bolus may be uncomfortable for the patient and difficult to reproduce. Chrétien et al. developed a unique translating bed technique that uses variable velocity to improve dose uniformity along the superior–inferior (sup–inf) axis of the patient. Despite large improvement in dose uniformity along the sup–inf axis, the variable velocity technique with rectangular fields cannot be used to improve dose uniformity in the transverse plane of the patient. More recently, helical tomotherapy has been used for the application of techniques such as intensity‐modulated total marrow irradiation (IM‐TMI) and total lymphatic irradiation for escalating dose to the bones and lymphatic system.An established requirement in TBI is to deliver a uniform dose to the entire patient body. Unlike standard radiotherapy techniques, achieving dose uniformity during TBI is a challenging task. Internal inhomogeneities, irregular body contours, and the large target size often result in dose uniformity no better than regimens.–6 No for application with a linear accelerator. During AM‐TBI, a dynamic multileaf collimator (DMLC) varies the two‐dimensional beam aperture while the patient is translated on a moving bed under a vertical radiation beam. Despite improved dose uniformity, the technique is not without shortcomings, with several issues limiting the accuracy of the fluence optimization, as well as impeding clinical deployment of the technique. While these issues are discussed in detail elsewhere, a brief description of some of the challenges with AM‐TBI is provided, as follows:The Eclipse‐based technique requires calculation of optimized fluence distribution using multiple static beams, making it difficult to implement clinically.The beam divergence effects resulting from the use of multiple static beams causes deviations from the optimal fluence along the sup–inf axis of the RANDO phantom.Errors in fluence optimization also result from the nonuniform beam profile in the sup–inf direction.Recently, we described a novel aperture modulated TBI (AM‐TBI) technique,15 fIn the current work, an advanced aperture modulated translating bed TBI technique has been developed. Radiological depths are calculated on individual RANDO phantom CT slices in MATLAB. Based on these radiological depths, beam apertures are designed using the DMLC. This novel TBI technique is referred to as aperture modulation based on Radiological Depths (RD‐TBI) and is compared throughout the paper to our previous technique, based on Eclipse fluence optimization, referred to as AM‐TBI.A flowchart summary of the both AM‐TBI and RD‐TBI techniques is given in An anthropomorphic RANDO phantom  was CT scanned using a Brilliance Big Bore spiral CT simulator  with 3 mm slice thickness. All CT slices were imported into MATLAB  and an external body contour was defined. From the body contour, entrance and exit points were determined for diverging rays, as shown in The diverging rays start at the X‐ray source position and pass through the plane of a CT slice. The distance separating these ray lines in the transverse plane at isocentre (100 cm) is equal to the MLC leaf width. d, is calculated using the following well‐known equation:The radiological depth along each ray line, di is the length of a segment with electron density ρi along the ray line through the CT slice. d′ is calculated for every ray line and over all CT slices.where The final radiological depth map for the entire RANDO phantom is presented in 15 cm/min under a vertical radiation beam with 300 MU/min dose rate. There is a linear relation between aperture length and absorbed dose for a given radiological depth. For the same aperture length along the direction of motion of phantom, the absorbed dose decreases with increasing depth. Combining these two concepts, aperture length can be adjusted to deliver similar doses at different depths in the phantom. Such a relation  MLC defined apertures were designed for each AP and PA irradiation. The number 143 corresponds to the length of the phantom (109 × 0.9 = 99 cm) plus 15 cm (17 × 0.9) on both ends for complete irradiation coverage. Selected apertures along RANDO are shown in Leakage through MLCs was not evaluated explicitly but was implicitly determined while generating K were derived using the concept of scatter maximum ratios (SMR). The mathematical expression is given in To account for the scatter contribution, scatter kernels, os (SMR).4 The rd is the field size at depth d, Sp is the phantom scatter factor, and TMR is the tissue maximum ratio. The scatter kernel K is determined using the following equation:where dref is set at 10 cm, and r2 and r1 are the radii of equivalent circular fields related to rectangular fields with length X and width Y as follows:where The radii are calculated from square beam data with the assumption that the area of both the equivalent circle and equivalent square are the same.4SMR and shape of the scatter kernel at 10 cm depth vs. radius of the beam, respectively. It is clear from K, with the radiological depth RD is performed using In order to determine the scatter distribution within the RANDO phantom, a convolution of the scatter kernel, The resultant scatter distribution is shown in In order to include the scatter contribution in the fluence optimization, all the beam apertures were scaled using the following equation:MLC leaf separation is the one calculated using Smax corresponds to the maximum relative scatter, and S is the relative scatter at any point in RANDO, as shown in where 300 MU/min) and constant bed velocity (15 cm/min).Due to the limitations of the treatment planning system for dose calculations in a dynamic environment, the dynamic irradiation was simulated as a number of static beam positions, as shown in Deviation of the calculated dose from the prescription (100 cGy) was determined using the following equation: with positional accuracy of ±0.1 mm. The speed and precise position of the bed are monitored in real time by a dual encoder system during irradiation. The radiation beam and bed motion are synchronized, such that if one fails, the other shuts off or stops immediately. The distance from the source to the bed surface is 205 cm. With bed motion in the cross‐plane direction, a collimator rotation of 90° was necessary to accomplish aperture modulation in the sup–inf direction. The Y jaws were positioned to cover entire width of the RANDO phantom in the lateral direction.A novel translating bed for TBI has been designed in‐house14 witDuring irradiation the apertures are dynamically modified as the phantom/patient is translated through the beam. Multiple static, MLC defined apertures are combined into a single dynamic MLC file for dynamic dose delivery. Every control point of the dynamic MLC file represents a single beam aperture, and because of the constant bed velocity and dose rate, each control point is equally weighted. Two such files were created, one for each AP and PA dose delivery. For a given dose rate and bed velocity, the treatment time was calculated in terms of MU. Clearly setup uncertainties and positioning uncertainties could compromise the uniformity of the dose distribution within the phantom/patient. This issue has been discussed elsewhere and will not be further addressed here.15Treatment plans were created by importing 143 AP/PA individual MLC files into Eclipse to deliver a 100 cGy dose to the midplane of RANDO. Each aperture was delivered with the same number of monitor units (18 MU each). For each AP/PA position, a total of 2574 MU was delivered within a total “treatment” time of 17 minutes. The treatment time for this technique is twice that of our standard TBI technique. However, using larger width apertures, the treatment time can be reduced at the expense of decreased dose uniformity.−7% to +3% along the suf‐inf axis of RANDO.±4% for the RD‐TBI with scatter correction. ±2% when the scatter correction is applied.The calculated beam apertures were then modified to account for the scatter contribution using  for details).The doses calculated by RD‐TBI with scatter correction applied were compared against those calculated by AM‐TBI Overall RD‐TBI technique with scatter correction provides more uniform dose distributions than AM‐TBI.With the RD‐TBI technique, instead of calculating the optimal fluence from Eclipse, beam apertures are modulated based on radiological depths and scatter corrections calculated on a slice by slice basis for the entire patient/phantom using MATLAB. Because we can automate the process in MATLAB, we significantly reduce user errors and greatly increase the efficiency of the process; the RD‐TBI reduces the amount of time spent on aperture shape design by a factor of 10. On average about 15 minutes are required to perform beam aperture optimization with this technique.Another significant issue with AM‐TBI results from the use of fewer, larger fields for fluence optimization. This is necessary from a practical standpoint because automation of such processes is not possible in Eclipse. The use of fewer, larger fields in the AM‐TBI technique causes deviations from the optimal fluence due to beam divergence effects and the nonuniform beam profile in the sup–inf direction. These two effects, both skewing optimal fluence along the RANDO phantom, are significantly reduced in the RD‐TBI technique because radiological depths are calculated for individual CT slices. The beam aperture for the same slice is optimized based on these radiological depths, mitigating the effects of beam divergence and beam profile in the sup–inf direction.Our results demonstrate that RD‐TBI technique, corrected for scatter, delivers a more homogeneous dose distribution to a nonuniform patient compared to AM‐TBI. The RD‐TBI technique is more practical and clinically viable. Beam aperture design with this novel technique offers a ten‐fold reduction in planning time compared to the AM‐TBI technique. No physical compensation is required, which makes it easy for the staff and comfortable for the patient. This assumption was the motivation for the present study.It is probably impossible to answer the question, Do more homogeneous dose distributions in TBI result in better clinical outcomes? As with IMRT and other advanced forms of dose delivery, we presume that a more uniform distribution around the prescription point results in better outcomes. Thus it is generally assumed that every effort should be made to deliver as uniform a dose distribution as possible for TBI. Point dose measurements were performed using LiF thermoluminescence dosimeters (TLD), placed at 29 different locations within the RANDO phantom. The phantom was then irradiated using the aperture modulated TBI technique. TLD measurements were compared with the calculations performed by Eclipse. Agreement between measurement and calculation was better than ±3%.The dose distribution calculated by Eclipse has been validated for the AM‐TBI technique in RANDO.15 Poi±5% along the RANDO sup–inf axis. A lower dose is calculated in the head region due to the lower scatter contribution compared to the abdomen. This reduced scatter is not accounted for during the simpler aperture modulation using K, were derived from the scatter maximum ratios (SMR) at 10 cm reference depth. Obviously the scattering pattern is different at different depths in a water phantom; however, the kernels determined at 10 cm depth are reasonable approximations of all depths and have previously been used by some investigators. As explained in the Methods Section, beam apertures are modified using the scatter distribution in RANDO.To improve the dose uniformity in three‐dimension, the scatter contribution was taken into account. Scatter kernels, nt depths17 in An inherent advantage of the aperture modulated TBI is achieving dose homogeneity in the lungs without any physical shielding . FurtherFor this phantom study, a machine dose rate of 300 MU/min was employed for reasons of experimental efficiency. This machine dose rate results in a dose rate at midplane in the RANDO phantom of 64 cGy/min. The optimum dose rate for clinical TBI is still a matter of debate, although some experts suggest it should be in the region of 10 cGy/min. Achieving such a dose rate for clinical applications is simply accomplished by reducing the machine dose rate to the desired level while, at the same time, reducing in the same proportion the bed velocity.A dosimetric comparison of the RD‐TBI corrected for scatter is made with AM‐TBI. Dose uniformity along RANDO midline is better with the RD‐TBI technique corrected for scatter than the AM‐TBI. A novel, aperture modulated TBI technique that employs dynamically shaped MLC‐defined beams based on radiological depth calculation has been developed. The new TBI technique minimizes the chances of error because the radiological depth calculations are automated for all patient/phantom CT slices. Dose uniformity in RANDO is greatly improved in three dimensions without using physical compensators. Results have shown that the dose distribution achieved with the RD‐TBI corrected for scatter is better than the AM‐TBI in three‐dimension. This technique not only generates a more uniform dose distribution, but it is also faster and more clinically viable than AM‐TBI.The authors would like to thank Marie‐Claude Lavallée, Mario Chrétien, and Luc Beaulieu of the CHUQ in Québec City, Québec, Canada for extremely useful discussions and for many helpful suggestions regarding the mechanical and electrical design of the translating bed. The authors also appreciate the thorough evaluation and thoughtful comments of the reviewers of this manuscript.


CVD) risk. CVD risk communication should improve patients’ understanding of risk and risk‐reducing behaviours; however, the effectiveness of risk screening is debated and evaluation currently limited.Unhealthy lifestyle is common in psoriasis, contributing to worsening disease and increased cardiovascular disease  determine proportions of CVD risk factors among patients with psoriasis at risk assessment and (ii) examine patient and practitioner experiences of risk communication to identify salient ‘process’ issues. Audio recordings of consultations informed in‐depth interviews with patients and practitioners using tape‐assisted recall, analysed with framework analysis.Mixed‐methods study in n = 287) undergoing CVD risk assessment; 29 patients and 12 practitioners interviewed.Patients with psoriasis (NICE recommendations: very high waist circumference (52%), obesity (35%), raised blood pressure (29%), smoking (18%) and excess alcohol consumption (18%). There was little evidence of personalized discussion about CVD risk and behaviour change support in consultations. Professionals reported a lack of training in behaviour change, while patients wanted to discuss CVD risk/risk reduction and believed practitioners to be influential in supporting lifestyle management.A high proportion of patients had risk factor levels apparent at risk assessment above CVD risk/risk reduction. Practitioners need training in behaviour change techniques to capitalize on ‘teachable moments’ and increase the effectiveness of risk screening.Despite high levels of risk factors identified, opportunities may be missed in consultations to support patients with psoriasis to understand  In the UK, the National Health Service (NHS) health check programmeet al.'s international Cochrane reviewHealth check attendance levels and treatment uptake have been lower than anticipatedStudies to evaluate the programme have so far been limitedPsoriasis is a complex, long‐term inflammatory systemic condition, presenting with a skin rash, affecting at least 2% of the UK population.Unhealthy lifestyle behaviours such as excess alcohol consumption,Perception of personal risk is highly complex and prone to systematic or error‐based biases.Qualitative research with healthcare practitioners shows that their personal attitudes towards/beliefs about health checks can be barriers to delivering lifestyle change support to patientsprocess of assessing for and communicating about CVD risk, using psoriasis as an exemplar of a condition where risk reduction in the form of lifestyle modification may be beneficial to disease management.This study aimed to explore patient and practitioner perspectives of the and below 40 years of age  in 13 general practices in North West England; and (ii) a ‘nested’ qualitative study of the process of risk communication in consultations for CVD risk assessment in people with psoriasis through in‐depth interviews with patients and practitioners, using excerpts from audio‐recorded risk communication consultations to assist questioning. People with psoriasis are not specifically targeted for CVD risk assessment; however, general practitioners (GPs) and practice nurses were asked to conduct risk assessment consultations in accordance with their usual health check procedures to capture routine practice.The study involved two elements: (i) CVD risk factor assessment of adult patients with psoriasis above General practices varying in size and locality were identified and recruited from five primary care trusts across North West England. Practices were reimbursed for their participation. Using Read codes known to map to psoriasis and medications/topical preparations for psoriasis, practices identified patients with psoriasis over 18 years old on their lists. Those with severe mental health problems, without capacity to consent, the recently bereaved and the terminally ill were excluded by the GP. Identified patients were invited to attend a CVD risk assessment at their practice. Smaller practices mailed all eligible patients on their list; larger practices mailed an agreed number (depending on practice capacity), in which case a random number list was used to select potential participants.Ethics approval was obtained from the North‐West Research Committee, Greater Manchester East (REC ref: 11/NW/0654). Patients expressing interest were telephoned by a researcher who explained the study and, with the patient's agreement, arranged a CVD risk assessment at their own practice. Consent to audio‐record the risk assessment and follow‐up consultations was sought from all participating practitioners and patients, with the aim of capturing as many recordings as possible across the sample. Participants whose consultations were recorded were sampled to undergo subsequent qualitative interviews on the basis of (i) consultations in which salient process issues were identified and (ii) diversity of personal characteristics. Practitioners were sampled to obtain a mix of GPs/practice nurses and patients for diversity on age and gender.On attendance at the practice, informed consent was acquired from patients and each completed a medical history questionnaire. The GP or practice nurse recorded a range of biomedical and behavioural measurements that are part of standard CVD risk screening procedures (see Table S1 for measurements recorded at risk assessment). Patients were recalled for a follow‐up discussion of their screening results if deemed necessary by the practice. The research team was informed if a follow‐up appointment was advised.Risk factor variables were derived from measured or patient‐reported data based on current published UK guidelines.Consultations were audio‐recorded and used to inform subsequent in‐depth interviews with practitioners and patients about their experiences of risk communication during consultations using ‘tape‐assisted recall’ (T‐A‐R).process issues (when and how CVD risk was discussed/addressed in the consultations) using a qualitative content analysis approach.a priori analysis framework of topics relevant to CVD risk assessment guided critical listening/coding of audio recordings (see Table S2). Coding enabled identification of instances when biomedical and behavioural factors as well as additional factors pertinent to this specific patient group such as psoriasis severity, quality of life and mood were discussed. Additionally, by coding the audio recordings, practitioners’ communication techniques could be categorized in terms of (i) acknowledgement of patient cues for discussion, (ii) general communication style and (iii) approaches to addressing issues connected to risk/lifestyle. The two authors each analysed 50% of the audio recordings and discussed all coding to resolve and agree codes for ambiguous examples. The content analysis enabled identification of how CVD risk was addressed within consultations to guide selection of T‐A‐R excerpts to inform subsequent qualitative interviews.Two authors (AC and CP) familiarized themselves with the audio recordings to identify Principles of framework analysis,Thirteen general practices participated. Practice size (number of registered patients over age 18) varied between 1086 and 16 746 patients. Practices were located in a variety of rural and urban areas and varied in levels of deprivation. From 1446 invitations for CVD risk assessment sent, 447 people responded and 287 attended an appointment , an overall attendance rate of 20%. Of those attending, 165 (57%) were female and the mean age was 53 years. Comparing those who did and did not attend, there was no difference in the proportion of women; however, a lower rate of attendance was recorded for the under 40s .evident at risk assessment and thereby amenable to discussion during the consultation. Table Biomedical data were analysed for proportions of risk factors in the sample . Risk assessments were generally conducted in dedicated clinics making audio recording straightforward; however, follow‐up consultations were conducted on an little evidence of detailed discussions about CVD risk (core issue 1). When patients offered cues about concerns related to risk factors , practitioners commonly responded by blocking or failing to pursue patients’ concerns, shutting down rather than opening up a dialogue. Secondly, practitioners demonstrated a focus on recording information rather than opportunistically addressing CVD risk reduction in consultations (core issue 2). This was evident in instances where a clear statement from the patient (e.g. consultation 101: ‘I'd love to lose a bit of weight to be honest’) elicited a disconnected practitioner response. Here the clinician appeared to be primarily fixed on documenting biomedical or behavioural data rather than incorporating the patient's agenda into the work of the consultation. Thirdly, little evidence of skilled patient‐centred practice was observed in consultations (core issue 3). Skilled practice was apparent in a minority . This was a rare example of a practitioner recognizing and acting upon an opportunity to increase the salience of possible behaviour change in the patient's mind and support their self‐efficacy. This practice nurse was one of only two practitioners (both practice nurses) who consistently picked up on and responded to openings in consultations to address CVD risk with patients.Analysis of the audio‐recorded consultations revealed three core issues during patient–practitioner interactions. Firstly, there was In summary, opportunities to discuss and address lifestyle behaviours such as smoking, diet and exercise which occur naturally in risk assessment consultations were often overlooked by practitioners in these recordings. Further extracts from the audio‐recorded consultations are presented in Table In‐depth interviews were carried out with 29 patients  and 12 practitioners  who had consented to have their consultations audio‐recorded (see Table S3 for characteristics of interviewed patients and practitioners). Interviews focused on patient and practitioner perceptions of CVD risk assessment/follow‐up consultations. Excerpts from the audio‐recorded consultations, including examples of instances when opportunities for discussion of CVD risk and/or risk reduction appeared to have been missed, informed questioning.Three key themes emerged from the analysis of the interviews: (i) limited shared discussion about CVD risk and lifestyle issues, (ii) limited provision of personalized risk reduction support to patients and (iii) the perceived influence of health practitioners in supporting risk reduction. These themes expand upon and illuminate the core issues  revealed by the consultation data. Each is described below alongside relevant data extracts which highlight key contrasts in patients’ and practitioners’ views about the process of CVD risk assessment.P12: Female, aged 45, obese, very high waist circumferenceI don't want to go [to doctor] just because I'm worried about diabetes or I want advice about my weight…because they're so busy and a lot of things you can get on the internet so rather than waste an appointment you just browse. P9: Male, aged 38, obese, very high waist circumferenceOn hindsight I could've said [to the practitioner] ‘what would you recommend I do…to see if I can reduce any potential cardio risks?’ I wasn't sure how far I should go with that conversation – was it relevant? Patients assumed that it was not their place to raise concerns in CVD risk assessment consultations because the process was essentially clinician‐ rather than patient‐driven. This led them to minimize the importance of risk and lifestyle‐related issues and contributed to the lack of discussion (core issue 1) apparent in consultations:P29: Female, aged 33, no risk factors seen at assessmentThey say at the end ‘have you got any questions?’ and then you've forgotten what's gone on previously…it's all hazy what's been said as well, you know? You're talking about your health so you are a bit apprehensive, forgetful. P18: Male, aged 57; obese, very high waist circumference, smoker, drinks alcohol (declined to disclose quantity)Maybe [practitioners] can help you with weight loss and all that but I suspect there's a lot more people they need to help before they help me losing some weight! Ultimately, it's your own responsibility. Furthermore, patients assumed that practitioners would view these issues as trivial and not a good use of their time. Some patients reported being too anxious to be able to raise health concerns with practitioners in the consultation and others seemed keen to preserve relationships with clinicians by not bothering them with ‘unimportant’ concerns:GP3From my point of view it was a data‐gathering exercise as opposed to a discussion about cardiovascular risk with the patient. Of course [patient] may have asked questions during that and if you had time you could try and answer. PN6I ask them to eat oily fish three times a week – religiously. Practitioners reported that their main focus in these consultations was on gathering information from patients and informing/educating them about healthy lifestyle behaviours with reference to government recommendations or advice. This suggests that they were less focused on patient‐led discussion in which they could use cues in consultations to talk about patients’ own concerns and explains the focus on information recording and lack of detailed discussion apparent in the consultations (core issues 1 and 2):PN1It's not very different from doing a blood pressure clinic in terms of questions we need to ask, information we need to find out from patients, and then the advice that we give to them, so from that perspective it wasn't a big challenge. It's just the fact that things like the tape recorder, I think that puts a different slant on it. PN2I saw it as more like a screening process really…like doing a well person's check, but the patient has psoriasis really. I do a lot of reviews anyway, like diabetic and heart reviews. So…to me it was a screening thing. Practitioners described the consultations undertaken for the current study as similar or equivalent to the routine health checks they would normally conduct. The only differences identified were as follows: (i) The target group was atypical ; (ii) more time was allocated for consultations than in normal practice; and (iii) the consultation needed to be audio‐recorded:Taken together, patients’ reluctance to instigate conversations with practitioners about risk‐related health concerns and practitioners’ focus on information gathering/advice giving meant that there was little shared discussion taking place during consultations that enabled patients to understand their risk status or ways to reduce risk. Practitioners reported that the conduct of the consultations differed little from that of customary health checks, suggesting that shared discussion may also lack prominence in routine practice.PN3I always treat it exactly the same. I don't change [information given]. It's just what I know is what I give out and that's it. That's as much as I do. GP2I don't know whether [what was said] is conveying any message…but certainly [patient] knows what his waist size is. We haven't discussed anything further about that so it's difficult for me to guess [what patient understood]. Practitioners reported that one of their roles is to provide standardized government recommendations and lifestyle advice to patients in CVD risk consultations:PN4Most people know what they should and shouldn't be drinking, eating, exercising – shouldn't they? PN7I think most people know where they're going wrong, they know that they shouldn't be eating three cakes every day…it's in the media all the time – get five a day in, take more exercise, eat less, move more – people know. There was limited evidence from practitioners’ accounts of tailored support being provided in response to specific information provided by individual patients, echoing the low level of skilled patient‐centred practice evident in consultations (core issue 3). It was notable that many practitioners expressed the view that their patients already possessed the knowledge required to understand and act appropriately to reduce CVD risk:P8: Male, aged 54, obese, very high waist circumference, 24 units weekly alcoholYou tend to think that unless there's actually something wrong, they don't call you in. Well that's always been my belief. P3: Female, aged 64, obese, very high waist circumferenceUntil I develop cardiovascular disease, I'm not going to take much interest…if it happens I'll deal with it then. Even when patients had several risk factors, they appeared not to prioritize discussion of them in the absence of current symptoms, with some seeing a need for action only once disease with perceptible symptoms had developed:not to change anything about their lifestyle, believing that the messages did not apply to them. This lack of individualized risk/lifestyle discussion in consultations (core issues 1 and 3) could lead patients to miss the personal relevance of health messages about CVD risk:P23: Male, aged 32, overweightIf [blood pressure] was high [PN] would probably say ‘well you need to look at eating this and cutting out that’. If there's nothing broken, then there's no need to fix it, is there? Some interpreted the lack of directive discussion by the practitioner as a signal Practitioners appeared to have a somewhat paradoxical standpoint in that they identified their role as providing standardized advice during CVD risk assessments, but at the same time, assumed patients already possessed the information required to make lifestyle changes. In contrast, patients often interpreted the absence of personalized engagement or advice from practitioners as a signal that the information was not relevant to or directed at them specifically, the implication being that they did not need to attend to risky health behaviours. This highlights the unintended consequences of the lack of detailed discussion and skilled patient‐centred practice found in the consultations (core issues 1 and 3).P11: Female, aged 52, obese, very high waist circumferenceI thought – I'm taking [PN's] word for it that where I am is good for me. I'm going to believe it because she's in that position where she'd know. Patients clearly perceived GPs and practice nurses as knowledgeable and competent both to help them understand CVD risk and make changes to lifestyle:Female, aged 62, obese, very high waist circumferenceI thought [GP] might've asked me a bit more about what I was doing, how I was losing the weight, what exercise I was doing, but he didn't. P19: Some patients said they had been keen to discuss their risk and lifestyle with their practitioner but had not been given the opportunity within their consultation:P12: Female, aged 45, obese, very high waist circumferenceI'd rather talk to a health practitioner than somebody at the gym who's stick thin, loads of muscles and a bit intimidating. So a nice normal average person who's got the information is a lot more comfortable. P8: Male, aged 54, obese, very high waist circumference, 24 units weekly alcoholIf a [health practitioner] says – ‘that's way too much mate, you shouldn't be having that much’ [alcohol], then you start thinking to yourself, hang on, he's a practitioner, I need to cut back a bit. Patients viewed primary care practitioners as approachable and trustworthy individuals with whom to appropriately discuss potentially sensitive concerns connected to body image or lifestyle behaviours, and perceived them to be in a position of influence in prompting their thinking on these issues:PN6With hindsight I should have definitely taken that further [discussion with female patient drinking 30 units of alcohol per week]. I find that really interesting for reflective practice…I am too people pleasing. PN3If they tell you they enjoy smoking I feel there's no point. They can't see the damage that's being done so they feel fine. You get ‘my granddad lived to be 102 and he smoked’. I can't say anything about that…you know that you're never going to get anywhere with them, so that's up to them. In contrast to this patient perspective, practitioners  reported views of themselves as lacking the power to effectively support patients with lifestyle changes. Nurses’ accounts highlighted a lack of confidence in broaching potentially sensitive behaviour change topics in case the patient–practitioner relationship was disrupted. In addition, they expressed pessimism about their degree of influence to motivate patients:PN4I think we do need more training because it's difficult to get these things across. PN7It's difficult to know what people understand because quite often they'll sit there and they'll agree with you and nod their head, but I don't know what they're thinking really. So I don't really know how else to deal with it. Furthermore, nurses suggested they were not well equipped to do such work, being unsure how to check patients’ understanding of risk/lifestyle issues. Only one nurse (PN9) had undergone specific, structured training in techniques to support lifestyle behaviour change. The remainder reported that a lack of training undermined their ability to undertake these tasks which they simultaneously identified as being key elements of their professional role. This offers insight into the lack of detailed discussion and skilled patient‐centred practice observed in the consultations (core issues 1 and 3):Patients viewed practitioners as being in a position to motivate them, to help them understand and address their CVD risk and to identify ways of reducing it. Moreover, they expressed the desire to address these issues with their GP or nurse. In contrast, GPs did not always perceive behaviour modification support as part of their role. Furthermore, practice nurses expressed very limited confidence to carry out these activities with patients. This means that patients are not benefitting from their attendance at CVD risk screening, a time at which the very data required to formulate a tailored risk reduction strategy is being collected and recorded by key healthcare professionals.This mixed‐methods study of CVD risk factor assessment in people with psoriasis in UK primary care highlights important gaps in current practices around CVD risk screening. In particular, it demonstrates that CVD risk screening appears to be limited to a data collection activity rather than viewed as one component of a broader intervention strategy to reduce CVD risk. There was little evidence that opportunities for effective risk communication between patients and practitioners in consultations were recognized and acted upon by the practitioners conducting risk assessments. This study goes some way to offering a potential explanation for the debated ineffectiveness of national health check programmes and may explain Krogsbøll and colleagues’ findingsOur study shows that despite significant levels of risk factors identified in study participants at risk assessment , opportunities to support patients to understand CVD risk and/or identify risk reduction strategies may often be overlooked in consultations. A key explanatory factor was that practitioners’ confidence to deliver personalized lifestyle behaviour change support was low. While this study was undertaken in the context of trying to reduce psoriasis‐associated comorbidities, these findings have broader relevance to our understanding of the role of CVD screening and health checks.processes involved in CVD risk assessment at the level of the individual consultation provides crucial detail which aids our understanding of the apparently limited effectiveness of general health checks which have been identified at the population levelhttp://www.makingeverycontactcount.co.uk/; NICE public health behaviour change guidance).A focus on the all the different risk factors,trust patients placed in them which influences responses to risk informationpersonally relevant informationKnown factors which assist patient perception and understanding of risk could have been used by practitioners in this study to take advantage of opportunities presented in consultations such as helping people to understand A particular strength of this study was the use of T‐A‐R methods to go beyond self‐report and enable exploration of what practitioners do in practice. This addresses a limitation identified in previous studies of CVD risk communication in primary care.A shift in the focus of screening consultations is needed to encompass effective discussions and interventions to address CVD risk factors including behavioural ones. This means going beyond information/advice giving to change people's beliefs and increase motivation to make lifestyle changes and improve cardiovascular health.process issues in risk assessment and encourage professionals to focus on helping patients understand the personal relevance of lifestyle behaviour choices, engage with the possibility of making changes and discuss individually appropriate strategies for change within the primary care consultation.Screening for CVD risks is an activity which provides opportunities to engage patients in discussions about their current and future health status and offers practitioners the chance to provide timely brief interventions to improve future health. The benefits of health checks may not have materialized because of a focus upon data recording rather than intervention. Before abandoning health check programmes, it is important to attend to key This article presents independent research funded by NIHR under its Programme Grants for Applied Research scheme (RP‐PG‐0608‐10163). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. CEMG is an NIHR Senior Investigator. CCG is part‐funded by the National Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care West Midlands.No conflict of interests has been declared.Table S1. Measurements recorded at risk assessment.Table S2. Consultation audio recordings: framework guiding critical listening/coding.Table S3. Characteristics of patients and practitioners interviewed.Click here for additional data file.


Synaptic dysfunction and loss is the strongest pathological correlate of cognitive decline in Alzheimer's disease (AD) with increasing evidence implicating neuropathological tau protein in this process. Despite the knowledge that tau spreads through defined synaptic circuits, it is currently unknown whether synapse loss occurs before the accumulation of tau or as a consequence. To address this, we have used array tomography to examine an rTgTauEC mouse model expressing a P301L human tau transgene and a transgene labeling cytoplasm red (tdTomato) and presynaptic terminals green (Synaptophysin‐EGFP). All transgenes are restricted primarily to the entorhinal cortex using the neuropsin promotor to drive tTA expression. It has previously been shown that rTgTauEC mice exhibit neuronal loss in the entorhinal cortex and synapse density loss in the middle molecular layer (MML) of the dentate gyrus at 24 months of age. Here, we observed the density of tau‐expressing and total presynapses, and the spread of tau into the postsynapse in the MML of 3–6, 9, and 18 month old red–green‐rTgTauEC mice. We observe no loss of synapse density in the MML up to 18 months even in axons expressing tau. Despite the maintenance of synapse density, we see spread of human tau from presynaptic terminals to postsynaptic compartments in the MML at very early ages, indicating that the spread of tau through neural circuits is not due to the degeneration of axon terminals and is an early feature of the disease process. Littermates expressing the EC‐tTA and Tg(tetO‐tdTomato‐Syp/mut4EGFP) to result in EC‐tdTomato/Syp‐GFP without tau expression were used as controls. PCR screening was used to genotype animals using primer pairs 5′‐ACCTGGACATGCTGTGATAA‐3′ and 5′‐TGCTCCCATTCATCAGTTCC‐3′ for the EC‐tTA transgene, 5′‐TGAACCAGGATGGCTGAGCC‐3′ and 5′‐TTGTCATCGCTTCCAGTCCCCG‐ 3′ for Tg(tetO‐TauP301L)4510 tau transgene, and 5′ CTT CAA GTC CGC CAT GCC CGA 3′ and 5′ TCC AGC AGG ACC ATG TGA TCG C 3′ for the EC‐tdTomato/Syp‐GFP transgene.Three to six  and presynapses from neurons overexpressing human tau (GFP) and fluorescently labeled secondary antibodies Table . For imm2) within the middle molecular layer of the dentate gyrus were generated. Image stacks were then binarized using thresholding algorithms in ImageJ. For total presynaptic and postsynaptic images stacks were binarized using an ImageJ script that combines different thresholding algorithms to select both high and low intensity synapses in an automated and unbiased manner . To calculate the synaptic density of both total presynapses and GFP‐positive presynapses, thresholded images were processed and analysed in MATLAB to remove background noise (objects present in only a single section were removed). The % GFP‐positive presynapses from each mouse was calculated as the sum of the number of GFP‐positive presynapses/sum total presynapses. To examine the spread of tau pathology, thresholded images were processed and analysed in MATLAB to remove background noise and to calculate the colocalization of Tau13 with postsynapses .Images from each set of serial sections were converted into image stacks and aligned using the Image J plug‐in, MultiStackReg  . All values are reported as mean and 2.3.2The % postsynapses colocalising with Tau13 from each mouse was calculated as the sum of the number of colocalization/sum total postsynapses within the MML. Group data for the colocalization of postsynapses with Tau13 was not normally distributed so the nonparametric Kruskal–Wallis test was performed (GraphPad Prism 5). The % synaptic pairs colocalising with Tau13 from each mouse was calculated as the number of pairs colocalising with Tau13/sum total synaptic pairs. Group data for the colocalization of synaptic pairs with Tau13 was not normally distributed so the nonparametric Kruskal–Wallis test was performed (GraphPad Prism 5). All values are reports as median and interquartile range.33.1Evident global synapse loss has previously been observed at 24 months of age in rTgTauEC mice  on the density of GFP‐positive terminals  within the MML revealed the presence of human mutant tau at the postsynaptic density Figure  of rTgTa4in vivo, tau can spread from presynaptic to postsynaptic elements without substantial loss of presynaptic terminals.The spread of tau inclusions through the brain occurs in a well‐characterized hierarchal pattern in AD and plays a role in the disease pathogenesis. Despite accumulating evidence supporting trans‐synaptic propagation of tau through neuronal connectivity (de Calignon et al., Several key questions remain to understand tau propagation through the brain including, which types of tau spread and what are the mechanisms of tau release from presynapses and uptake from postsynapses? Many forms of tau have been observed to be secreted in vitro including phosphorylated tau (Pooler, Phillips, et al., The uptake of tau by neighboring postsynapses ultimately induces neurofibrillary tangles within downstream neurons via as yet unknown templating or seeding mechanisms. These intracellular inclusions correlate with the cognitive decline and neuronal loss observed in AD (Arriagada, Growdon, Hedley‐Whyte, & Hyman, Despite the many questions that remain surrounding the propagation of tau through the brain, it is clear that tau spreads through the brain, likely via synaptic circuits. A promising therapeutic avenue is to prevent the spread of tau using immunotherapies (Gerson & Kayed,


Only 5% of adults consume the recommended level of dietary fiber. Fiber supplements appear to be a convenient and concentrated source of fiber, but most do not provide the health benefits associated with dietary fiber.This review will summarize the physical effects of isolated fibers in small and large intestines, which drive clinically meaningful health benefits.A comprehensive literature review was conducted (Scopus and PubMed) without limits to year of publication .The physical effects of fiber in the small intestine drive metabolic health effects , and efficacy is a function of the viscosity of gel‐forming fibers . In the large intestine, fiber can provide a laxative effect if (a) it resists fermentation to remain intact throughout the large intestine, and (b) it increases percentage of water content to soften/bulk stool .It is important for nurse practitioners to understand the underlying mechanisms that drive specific fiber‐related health benefits, and which fiber supplements have rigorous clinical data to support a recommendation.For most fiber‐related beneficial effects, “Fiber needs to gel to keep your patients well.” These studies compare subpopulations  and look for statistical associations with decreased or increased incidence of disease. The adequate intake guidelines for dietary fiber are based on a significant association between a high‐fiber diet and a reduced risk for cardiovascular disease , it is important to recognize that population‐based data lack the control necessary to establish causation. These studies can only establish statistical associations, so it is not possible to determine to what degree an observed physiologic effect is directly attributable to the fiber component of the diet, versus other health‐promoting components such as micronutrients, phytochemicals, or a reduction in fat/calorie intake. In contrast to whole foods, the physiologic effects of an isolated nondigestible carbohydrate  can be readily assessed for a direct effect in a placebo‐controlled clinical study. The purpose of this review is to provide nurse practitioners with an understanding of (a) the physical effects of isolated fibers in different regions of the gut that drive each specific health benefit, (b) which specific fibers possess the physical characteristics required to provide each specific health benefit, and (c) which specific fiber supplements are supported by rigorous evidence of a clinically meaningful health benefit.2  and fasting blood glucose  versus placebo. These gel‐dependent glycemic effects were additive to the effects already conferred by a restricted diet and stable doses of prescription drugs (a sulfonylurea and/or metformin). To optimize the glycemic effect, the gel‐forming fiber should be dosed with meals.While postprandial glucose studies are useful for assessing the acute glycemic effects of fiber, longer (multimonth) intervention studies are needed to determine if a gel‐forming fiber can provide a clinically meaningful improvement in glycemic control in patients at risk for, or being treated for, type 2 diabetes mellitus. Numerous multimonth clinical studies demonstrate a clinically meaningful reduction in fasting serum glucose, insulin, and HbA1c for a gel‐forming fiber versus placebo in patients with metabolic syndrome and type 2 diabetes  and HbA1c  in patients being treated for type 2 diabetes ; a modest effect in prediabetes , and the greatest effect in patients with type 2 diabetes  versus placebo. Note that insoluble fiber (wheat bran) was used as a placebo. Insoluble fiber and low‐viscosity/nonviscous soluble fiber  do not provide this viscosity/gel‐dependent beneficial effect. It should also be noted that viscosity alone, without gel‐formation, does not confer a cholesterol‐lowering benefit. A well‐controlled clinical study in 105 patients with hypercholesterolemia  assessed the cholesterol‐lowering efficacy of a natural viscous/gel‐forming fiber (psyllium) versus a viscous but nongel‐forming semisynthetic fiber  and a synthetic polymer , all dosed three times a day before meals for 8 weeks , but not for the methylcellulose or calcium polycarbophil treatment groups.The importance of viscosity for gel‐forming fibers was demonstrated in a clinical study that assessed the cholesterol‐lowering efficacy of oat bran (β‐glucan) cereals processed to three different viscosities  in 345 subjects , and equivalent to a higher dose of simvastatin (20 mg/day) alone  in 141 patients with metabolic syndrome, patients were fed an American Heart Association Step 2 diet alone (control group) or the same diet supplemented with psyllium or guar gum  and stool output (assessed as grams of stool per day). The consistency of stools is dependent on stool water content, and small changes to stool water content result in large changes to stool consistency ; and (b) soluble gel‐forming fiber  retains its high water‐holding capacity to resist dehydration throughout the large bowel  on stool parameters McRorie, . In contMcRorie, . Both meMcRorie, . FermentMcRorie, . Methylcstool normalizing effect (softening hard stool in constipation and firming loose/liquid stool in diarrhea) has been shown to be effective for normalizing stool form in patients with IBS  effectively lowers elevated serum cholesterol, and improves glycemic control in patients with metabolic syndrome and type 2 diabetes. Low‐viscosity/nonviscous soluble fibers  and insoluble fiber  do not provide these viscosity‐dependent health benefits. In the large intestine, fiber must resist fermentation to remain intact in stool and significantly increase stool water content, in order to provide a laxative effect. Large/coarse particles of insoluble wheat bran can provide a mechanically irritating effect, stimulating the mucosa to secrete water and mucous. Nonfermented gel‐forming psyllium retains its high water‐holding capacity to provide a dichotomous While it is reasonable to recommend a high‐fiber diet, only about 5% of Americans consume the recommended level of fiber. Fiber supplements may appear to be a healthy option to increase fiber intake, but clinical evidence supports that most fibers in supplements do not provide any of the health benefits associated with a high‐fiber diet. It is therefore important for nurse practitioners to recognize the physical characteristics of isolated fibers that drive specific health benefits . It is also important to recognize which marketed fiber supplements have rigorous clinical evidence of one or more clinically meaningful physiologic effects Table . Most of


There is increasing interest in using data from oral food challenges (OFC) performed under medical supervision to assist in allergy risk management, both in industry  not the immediate preceding dose but a dose given 1–2 h beforehand.Much of this seems logical, although there are clearly limitations: we do not yet understand the inherent variability and reproducibility of an individual's allergen threshold, although useful data will be generated by the TRACE Peanut Study NCT01429896). The OFC scenario is very different from ‘real‐life’ exposure: consumption of incremental doses of allergen at regular intervals  during OFC may induce a transient desensitizing effect leading to an overestimation of the MED 96. The Onot more at risk of anaphylaxis, something which seems counter‐intuitive to clinical experience In much the same way that previous reactions do not predict the severity of future reactions We (BKW) have previously reported a cohort of children who underwent OFC to peanut We have conducted a further analysis of this cohort, with reference to both the dose causing any symptoms versus that triggering anaphylaxis. We have also enriched the cohort with peanut‐allergic children undergoing double‐blind, placebo‐controlled food challenges according to international consensus Those who experience nonanaphylactic symptoms despite consuming the top dose Fig. . WhetherIndividuals who experience initially mild symptoms, but develop anaphylaxis with further exposure.Allergic individuals who develop anaphylaxis as their initial symptom (often without preceding subjective symptoms), a phenomenon which can occur at all dosing levels.We interpret these data as suggesting that individuals may have a threshold of reactivity for both any symptoms and a further threshold for symptoms of anaphylaxis Fig. . In someA major premise of OFC is the assumption that the procedure effectively dose‐limits the risk of anaphylaxis. Our analysis implies that this probably holds true at an individual level, for most allergic individuals. It is important to consider how cofactors or augmenting factors The current PRACTALL recommendation for a seven‐ to eight‐dose OFC protocol can be time‐consuming in clinical practice. Clinicians may be tempted to use a lower number of doses in a lower risk, routine clinical setting where OFC are used to rule out clinical allergy  and the completeness of the data set analysed. Despite a wealth of OFC data being reported in the literature, the quality of these data is not always apparent. In many cases, individual threshold data are not in the public domain; as a result, attempts to analyse the dose–severity relationship can be misleading. Zhu et al. analysed MEDs in the literature relating to individuals undergoing OFC and compared these to the severity of symptoms experienced. They reported that peanut‐allergic individuals experiencing severe reactions had significantly higher MEDs than those with more mild reactions Given the inherent risks of OFC, it is time that data relating to MEDs (particularly that arising from publicly‐funded research) are made freely available through a data‐sharing scheme, a scenario being proposed by leading medical journals PJT is in receipt of a Clinician Scientist award funded by the UK Medical Research Council (reference MR/K010468/1) and is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR or the Department of Health. PJT is a member of an industry‐sponsored ILSI expert group on predicting reaction severity.All authors declare no conflict of interest.This article was co‐written by PJT and BKW, who both approved the final version.


We read with great interest an editorial article on sexual function of patients with heart failure (HF) by Tiny Jaarsma published recently in your journal,According to the last European Society of Cardiology Guidelines, HF is a clinical syndrome that refers to a wide range of patients: those with HF and preserved ejection fraction (EF) (≥50%—HFpEF), those with an EF in the range of 40–49% (mid‐range HF—HFmrEF), and those with HF and reduced EF (<40%—HFrEF).On the other hand, sexual function in HFpEF and HFmrEF patients has not been studied sufficiently, and existing results of studies comparing sexual function of patients with preserved or decreased left ventricular EF are not representative as they were not designed for HF populations.