HART‐computed DVH data was validated against manually extracted data from the planning system for five head and neck cancer patients treated with the intensity‐modulated radiation therapy (IMRT) technique. HART calculated over 4000 parameters from the differential DVH (dDVH) curves for each patient in approximately 10–15 minutes. Manual extraction of this amount of data required 5 to 6 hours. The normalized root mean square deviation (NRMSD) for the HART–extracted DVH outcomes was less than 1%, or within 0.5% distance‐to‐agreement (DTA). This tool is supported with various user‐friendly options and graphical displays. Additional features include optimal polynomial modeling of DVH curves for organs, treatment plan indices (TPI) evaluation, plan‐specific outcome analysis (POA), and spatial DVH (zDVH) and dose surface histogram (DSH) analyses, respectively. HART is freely available to the radiation oncology community.A Histogram Analysis in Radiation Therapy (HART) program was primarily developed to increase the efficiency and accuracy of dose–volume histogram (DVH) analysis of large quantities of patient data in radiation therapy research. The program was written in MATLAB to analyze patient plans exported from the treatment planning system PACS numbers: 87.53.‐j; 87.53.Tf; 87.53.Xd. Modern radiotherapy techniques include 3D conformal radiation therapy (CRT), intensity‐modulated radiation therapy (IMRT), and image–guided radiation therapy (IGRT). The evaluation of CRT and IMRT plans requires an in‐depth analysis of isodose distributions, dose conformality indices, normal tissue complication probabilities (NTCP), and tumor control probabilities (TCP). Conformality indices and outcome‐based plan evaluations  are dependent on dose‐volume histogram (DVH) analysis. The clinical use of DVHs for the treatment of head and neck, breast, lung, pancreas, liver, and prostate cancers has been well reported in the literature.–5 ThA DVH represents a frequency distribution of average dose values over a 3D matrix of voxels composed of planning target volumes (PTVs) or critical structures within the patient anatomy.HART  program is an automated computational environment that was developed for the precise computation of dose‐volume statistics for a large quantity of patient data used for radiation therapy research. It was originally designed to expedite the extraction and analysis of DVH data from a swallowing physiology study involving 150 to 200 head and neck cancer patients treated with IMRT. Manual extraction of all the DVH data points of interest directly from the TPS was very time‐consuming and prone to error. Scripting within the planning system could also achieve the similar extraction results but would not provide the same flexibility and functionality for DVH analysis.) and accurately calculates differential and cumulative DVHs . It will query the user for arbitrary selection of DVH data points of interest and summarize the output in a simple spreadsheet format. This paper describes the development of the software (HART) and assesses its performance by comparing the results with manually extracted data from a commercial TPS. Furthermore, it also presents various aspects of treatment plan evaluation tools introduced into the program. Additional features include optimal polynomial modeling of DVH curves for organs, IMRT treatment plan indices (TPI) evaluation, spatial DVH (zDVH) and dose surface histogram (DSH) analyses, and plan‐based outcome analysis (POA) of various treatment schemes in a complete software package.HART reads in the primary dose grid data from the planning system in the American Association of Physicists in Medicine/Radiation Therapy Oncology Group (AAPM/RTOG) format  aPinnacle3 TPS  was used for IMRT planning of the patients enrolled in this study. The patients were treated using a sequential IMRT boost (SqIB) technique for three target volumes.Planning target volume 1 (PTV1) refers to the gross tumor volume (GTV) plus the high‐ and low‐risk regional nodes with their corresponding clinical target volumes (CTVs). CTVs were defined in the region of 3 to 7 mm margin above the boundary of corresponding GTV or regional nodes. Further 3 to 5 mm margins were also added to the corresponding CTVs to draw the boundary of PTV1 region.Planning target volume 2 (PTV2) includes the same GTV as mentioned above, and high‐risk regional nodes and their corresponding CTVs. CTVs were defined in the region of 3 to 7 mm margin above the boundary of corresponding GTV or high‐risk regional nodes. Further 3 to 5 mm margins were added to the corresponding CTVs to draw the corresponding boundary of PTV2 region.Planning target volume 3 (PTV3) includes only the GTV and its corresponding CTV. CTV was defined in the region of 3 to 7 mm margin above the boundary of corresponding GTV. A 3 to 5 mm margin was added to the CTV to draw the corresponding boundary of PTV3 region.This project was designed to support the analysis of an NIH‐funded, multi‐institutional study examining the swallowing function of head and neck cancer patients treated with IMRT. The  volumes.,10PAn IMRT plan was designed for the three target volumes . A typical IMRT plan for a head and neck cancer patient is illustrated in Fig. Similar planning criteria were also employed in designing PTV1, PTV2, PTV3 IMRT plans and a four field PELVIS plan for ten prostate cancer patients. The three planning target volumes  were designed for IMRT boost in prostate gland during the treatment. The prescribed doses (PDs) were 900 cGy–1440 cGy for PTV1, 900 cGy–1080 cGy for PTV2, 360 cGy–800 cGy for PTV3, and 4500 cGy for PELVIS plan, respectively. The dose fractionation was 180 cGy given twice a day on a week‐on/week‐off basis as per the institutional protocol approved by IRB. Rectum and bladder were the major critical organs contoured in the IMRT plans for the prostate patients.TCP_NTCP_CALC). It offers the following major advantages over other similar commercial high level systems: (a) syntax flexibility, (b) convenient user interface, (c) user‐friendliness, (d) advanced simulation features, (e) fast algorithm development, (f) compatibility with running networks and various operating systems, (g) multidimensional array computation, and (h) an economical software. HART formats RTOG data file information and stores them in simpler text file formats in the MATLAB platform as objects, groups, and classes.HART computation was performed on a PC with a processor speed of 1.8 GHz, 1024 MB of RAM, and Pentium (R) 4 CPU using MATLAB (version 7.5). It uses the advanced graphical features and simulation systems available in MATLAB . MATLAB provides a flexible platform to set up a computational and graphical environment for other secondary software such as HART, Computational Environment in Radiotherapy Research (CERR), and radio‐biological outcome evaluation tool  contoured in the specific type of images (such as computed tomography (CT) scan, fused positron emission tomographic (PET) / CT images) imported into the TPS. The program also computes the accurate number of voxels in a 3D contour of an organ or target described in RTOG data format for a radiotherapy treatment plan. Simultaneously it also performs the appropriate sampling of dose within a given number of contours to generate the dDVH for the corresponding organ or target. The dDVH matrices are stored as double or floating point numerical array formats for all corresponding organs. All dDVH matrices are converted into cDVH matrices in suitable dose constraint formalism. User‐selected data points are automatically computed and simulated simultaneously for each point of interest using the DVH computation technique, as will be discussed in the next section. The automatically formatted DVH results are eventually stored in a spread sheet output format in a user‐designated location as shown in Table The flow of information within HART is also summarized in Figs. HART reads in the treatment plan files with the AAPM/RTOG format and reorganizes the data into a simplified series of matrices. It then transforms the dDVH matrices into cDVH matrices. This is accomplished by summing up all differential voxels in a given dose range for each point of interest in the AAPM/RTOG header file. The software computes the absolute and fractional volumes of a target or critical structure receiving a dose of a certain amount using the cDVH data. The ideal dDVH for a target structure would be an infinitely narrow peak at the PD. For critical structures, this peak would ideally exist at 0 cGy. However, several peaks in a real dDVH indicate that different parts of an ROI are receiving different doses due to the local constrain and the inhomogeneous nature of the tissue.The smoothness of a cDVH curve depends on the bin size of the dDVH. A cosine interpolation technique with a weight factor of 0.5 was found to be a precise smoothing transition function between adjacent dose bins in the algorithm. The interpolation technique calculates the data point at the middle of two adjacent voxel elements corresponding to the adjacent dose bins in a particular ROI of the histogram. A polynomial curve fitting technique also acts simultaneously with the interpolation technique in order to find the optimal solution. The iterative piecewise polynomial fitting technique takes into account of the interpolated data point along with a series of six adjacent and nearest neighboring data points in the specified ROI of cDVH curve. This method of DVH computation employing a piecewise polynomial fitting technique and a cosine interpolation technique is the basis for the extraction of the user‐defined DVH parameters from the continuous cDVH curves in HART. This iterative process also determines optimal polynomial fitting model utilizing all cDVH data points for the corresponding target or critical structure as shown in Fig. Pinnacle3 system at 4 mm dose grid resolution for five head and neck protocol patients. NRMSD tests were performed for comparison of measured data from Pinnacle3, and HART extracted data for absolute and normalized volumes at four different points in critical structures and six different points in targets. Similarly, DTA tests were also performed for the comparison of measured data points and HART extracted data points in the high‐dose gradient regions, specifically when the NRMSD error was greater than 1%.The fundamental techniques, such as normalized root mean square difference (NRMSD) and distance to agreement (DTA), were utilized to assess the HART‐computed results and the subsequent error analyses. These results were further validated by manually extracting the DVH statistics data for over 4000 specific parameters such as minimum dose, mean dose, maximum dose, and volumes coverage from the  than 1%.,12DVHs are strong tools for three‐dimensional treatment plan evaluation. However, the drawback is the loss of spatial information. In order to achieve two‐dimensional dose distribution information across various planes and surfaces of an organ, zDVH and DSH analyses are the best evaluation techniques for CRT and IMRT plans. The zDVHs provide the spatial variation of the dose as well as the differential dose volume information along the z‐axis with respect to the CT slice positions. DSHs provide the spatial variation of the dose in a surface perpendicular to the z‐axis in the ROI of an organ.HART accounts for all of the primary dose grid information and the 3D coordinate geometry of the target and critical structures. The algorithm generates dDVHs (secondary data) to create the corresponding cumulative DVHs, DSHs, and zDVHs. The DSHs and zDVHs help identify “hot” and “cold” regions within each slice of the target or normal structure of interest.zDVH by summing over the z‐coordinates z1,z2…zn, respectively.Di is a specific dose coverage in a particular CT slice at z‐coordinate position (zn).It should be noted that the DVH may also be obtained from High precision radiotherapy treatments such as CRT and IMRT have been frequently used in clinical routines in the past decade. In order to maintain the precision and quality of these treatments, it is essential to perform accurate patient mapping including target and organ volumes, patient immobilization, and treatment delivery utilizing an optimal treatment plan. The search for a single parameter to quantify the quality of a radiotherapy treatment plan has been ongoing but, as of yet, unsuccessful. In this perspective, a simpler method of treatment plan indices (TPI) evaluation technique of radiotherapy treatment has been incorporated into HART. A universal plan indices (UPI) set has been defined by summarizing various recognized plan indices for plan evaluation of radio‐surgical treatments, Gamma Knife (GK) treatments, and conventional LINAC‐based treatments.PTVPD is the PTV coverage at PD, and PTV has usual meaning.Target coverage index (TCI). TCI accounts for the exact coverage of PTV in a treatment plan at a given prescription dose as expressed below:V(OARi)≥ TOL is the fractional volume of ith organ at risk (OAR) receiving more than tolerance dose (TOL), and the relative weight (wi) of fractional volume of each organ is 1/N.Critical organ scoring index (COSI). COSI is a measure of both target coverage and critical organ overdose.PTV0.95PD is the PTV coverage at 95% of PD.Radiation conformity index (RCI). RCI gives a consistent method for quantifying the degree of conformity based on isodose surfaces and volumes.PITV>1 and PITV<1 refers to the over treatment and under treatment regions, respectively. But it fails to account properly for the relative position of PIV with respect to PTV in radio‐surgery and LINAC‐based plans.Prescription isodose target volume conformal index (PITV). PITV assesses the conformity of a treatment plan. It can also be expressed as:DMax is the maximum dose point in PTV. Similarly D95 and D5 are the dose coverage at 95% and 5% volume of the PTV, respectively.Dose homogeneity index (HI). HI scales the “hot” spots in and around the planning target volumes.,18 IConformality index (CI) and conformation number (CN). CI measures the conformity of a treatment plan. CN accounts for the relative measurement of dosimetric target coverage and sparing of normal tissues in a treatment plan.,,20Target volume ratio (TVR). TVR is an objective measure of how well the prescription isodose line conforms to the size and shape of the planning target volume.PTV0.50PD is the planning target volume coverage at 50% of PD.Dose gradient index (DGI). It examines the steepness or shallowness of dose fall off in target volume.New conformity index (NCI). NCI and HI allows for the quick and simple comparison of different radio‐surgical treatment plans designed within the same or diverse radiosurgical systems, such as between LINAC and Gamma Knife.The overall quality factor (QF) of a plan can also be determined by a linear combination of all plan indices in the UPI set. These indices can be assessed by utilizing the DVH statistics extracted in the HART. QF can be efficiently computed for a plan by assigning the relative weights to all UPI plan indices as a complete plan evaluation strategy. Plan indices in UPI set can be systematically described as follows:Xi=, for a number of N major plan indices (N=10). The number (N) can be arbitrarily selected from UPI set for treatment plan evaluation in HART.Thus UPI set can also be simply expressed as,(Wi) can be adjusted between zero to unity for all relatively weighted indices {Xi} for a user defined number of indices (N) in the UPI set. The analytical expression in the argument of the exponential function in Eq. The quality factor (QF) of a treatment plan can be analytically expressed in terms of combination of above set of UPI indices as given below:HART offers a convenient feature for plan‐specific outcome analysis (POA) of the radiotherapy treatments. The program employs TCP and NTCP biological modeling for the overall outcome analysis of IMRT treatments. Local TCP can be evaluated by using the Poisson statistics model, and NTCP can be evaluated by using the sigmoidal dose response (SDR) model based on equivalent uniform dose (EUD) techniques proposed by JT Lyman.(vi) of a tumor target irradiated with a dose (Di) in the Poisson statistics model. Furthermore, the overall TCP takes into account of the cell survival fractions assuming the single hit mechanism of the cell damage. It can be expressed as:γ50 are the dose and normalized slope at 50% probability of tumor control in the target. HART utilizes the expression Eq. The necessary and sufficient conditions for a TCP model require the killing of all tumor clonogens. Assuming the heterogeneous irradiation in the tissues, the overall TCP is defined as the product of the probability of killing all clonogens in each differential volume element ϕ[EUD−TD50mTD50], best describes the SDR model to determine the NTCP indices for critical organs irradiated during radiotherapy treatments, as expressed below:The probit function, eatments,,23 am controls the slope of the dose response curve, and TD50 determines the position of a dose response curve at 50% chance of complication in the critical structure. Furthermore, GMD can be expressed as:n determines the dose‐volume dependence of a tissue which is deterministic for differences in tissue architecture. The expression Eq. The EUD or the generalized mean dose (GMD) represents the dose that, if delivered uniformly to the normal tissues or to the entire critical structure, would produce the same effect as the heterogeneous dose distribution as specified by the DVH. The parameter The above method, as proposed by Lyman for DVH reduction to a single dose GMD irradiated to an entire volume of an organ, is analogous to the Kutcher‐Burman (KB) reduction scheme for a non‐uniform DVH to a uniform one with an effective volume, and a reference dose equal to the maximum dose delivered to the organ.,23Manual extraction of over 4000 DVH points of interest requires 5–6 hours for each patient plan. HART accomplished the same number of computations and simulations in 10–15 minutes. Table Furthermore, features such as optimal polynomial fittings of cDVH curves for organs, TPI evaluation techniques, and POA options have been incorporated into HART. It has also been designed to perform various derivatives of DVH analysis such as zDVH and DSH analyses of the treatment plans. This information would be useful for the microscopic and macroscopic study of organ complication and local TCP following radiation therapy.Pinnacle3.DVH data calculated by HART fell within an agreement of 1% NRMSD or 0.5% DTA with the manually extracted data. Figure Pinnacle3 is dependent on the dose–grid resolution selected for a particular treatment plan. HART automatically adjusts to the Pinnacle3‐based dDVH bin size for the interpolation of data points. An optimized polynomial equation performs a precise estimation of an exact number of voxels corresponding to a given dose in the continuous DVH curve in HART.The accuracy of a DVH depends on the accuracy of the dose calculation, interpolation of dose matrices, and regression of the localized fittings. The dDVH computed in Pinnacle3‐extracted cDVH data points, especially in high‐dose gradient regions. This technique was efficient for precise computation of DVH statistics from cDVH curves in comparison to other conventional data interpolation techniques such as linear, cubic, or hermite interpolations.NRMSD was calculated with a limited number of data points extracted from the cDVH curves. It should also be noted that the greatest errors were observed in the regions of high‐dose gradients due to lack of exact DVH statistics estimation methodology. But the data points estimated using the optimal polynomial equations determined for the cDVH curves were found to be in good agreement with the Pinnacle3 as gold standard. NRMSDs evaluated for HART‐extracted cDVH data points utilizing above methods for various targets and organs have been presented in Table NRMSDs were computed for two different cases by extracting cDVH data points using interpolation and optimized polynomial fitting of the same cDVH curves, assuming manually extracted cDVH data statistics in Manual extraction of the DVH data was prone to approximately 5–10 human errors for each patient during the extraction of over 4000 DVH data points. The human errors were successfully eliminated by automating the extraction process using the HART program. The automated process included importing and reformatting the AAPM/RTOG data, cDVH computations, graphical illustration of dDVHs and cDVHs, and exporting the extracted data into a simple spreadsheet format. The program considerably shortened the execution time for DVH analysis. A comparison between manual extraction and HART computation of the sample DVH data is shown in Table As discussed earlier, HART‐based optimal polynomial simulations for cDVH curves can also be utilized to identify precise dose response models for various critical organs in radiation therapy research. The software also offers a simple format for treatment plan indices (TPI) evaluation. UPI score in TPI functionality determines the values of individual plan indices in the UPI set. These relative scores of indices evaluate different aspects on dose homogeneity and target coverage in a treatment plan. Users have the option to select the number and type of indices to be included in the evaluation process. The ideal UPI scores for all plan indices should be unity. The overall performance of the plan indices in the UPI set can be performed by evaluating the QF for a complete plan, as discussed earlier. Typically QF equals to unity for an ideal plan, whereas the deviation from unity refers to underdose or overdose treatments in the corresponding plan. A simple demonstration for DVH statistics‐based plan evaluation technique and the quality factor assessment for a typical IMRT treatment plan designed for a prostate cancer patient has been shown in Fig. (–) NTCP can be evaluated using sigmoidal dose response model (JT Lyman) and the overall TCP can be evaluated using Poisson statistics model, as displayed in Fig. Furthermore, this software has also incorporated a simple and user‐friendly plan‐based outcome analysis tool to examine NTCP of critical structures and TCP in a treatment plan as discussed earlier.–26 NDVHs provide statistical dose volume information and are unable to provide guidance on the location of “hot” and “cold” spots within a specific ROI. HART extracts the raw dDVH data within each CT slice, as well as gross dDVH data for normal structures contoured in a plan. So zDVH analysis can be utilized to evaluate the index of dose uniformity in such regions. Furthermore, DSH analysis is useful to study the dose distribution in serial organs such as rectum and esophagus, and parallel organs such as bladder and lungs. The results obtained from zDVH, DSH, and conventional DVH analyses would be very much useful to perform an in‐depth evaluation of treatment plans, and to study the correlation of radiation toxicity with the organ failure and local tumor control probability. Figure User‐defined DVH computational moduleAbility to read standardized AAPM/RTOG data file formatsPortability in UNIX and Windows platformsUser‐friendly graphical interfaceStructure‐specific DVH analysis optionsCustomized spreadsheet outputThe dDVH data computational capabilityOptimal polynomial modeling for DVH curvesThe DSH and zDVH analysis modulesPlan indices evaluation modulePlan‐specific TCP/ NTCP outcome analysis toolHART is a reliable and efficient tool for DVH‐based analysis in radiation therapy research. Figure Pinnacle3 for a large number of patients, HART was developed as an alternative tool designed for customizable DVH data statistics computational functionality. Its application has been diversified by introducing optimal polynomial fitting model for DVH curves, TPI features, sDVH and DSH analyses, and flexible POA options of IMRT and CRT treatment plans in radiation therapy research. An illustration of statistical analysis of dose distributions in target and various critical structures utilizing HART extracted DVH data statistics for twenty head and neck cancer patients and ten prostate cancer patients has been presented in Figs. Since HART is not a stand‐alone executable software tool, the user needs to use MATLAB to run the program with any version of Windows or Linux operating systems. HART is also a cost‐effective and an efficient DVH analysis module. Another useful tool, CERR , was developed for plan viewing and image analysis purposes but not specifically for DVH data statistics computational purposes. Because of the DVH computational limitations in CERR and other similar tools, along with the time consuming and error prone process of data extraction from Pinnacle3. Thus various users would have the privilege of using the proposed automated tool independently on a simple MATLAB environment for multipurpose analysis.In general, HART is a simple, user‐friendly and useful tool for summarizing and quantifying dose‐volume distributions from CRT and IMRT treatment plans. It is specifically useful in handling a large number of patient data analyses for radiotherapy research. Furthermore, by synchronizing HART with MATLAB's DICOM‐RT toolbox and other available open source tools such as CERR, we can establish a powerful platform for DVH analysis in radiation therapy research. It could also provide a convenient medium for sharing research results among radiation oncology groups. An open source environment has been established so that various users can explore HART applications to other treatment planning systems. At present, the software requires a minimal code reconfiguration for compatibility with designated treatment planning systems other than Pinnacle3 TPS and exporting user‐defined cDVH data to a spreadsheet format. HART extracts DVH data points by utilizing noble DVH computational techniques. These results were found to be in excellent agreement with manually extracted data points from Pinnacle3. Clinically, HART provides an automated system that is ideal for examining numerous DVH statistics for multiple patients and a large number of critical structures. It can also perform optimal polynomial simulations for DVH curves in order to identify accurate dose response models for various organs. Furthermore, multidimensional DVH derivative features such as zDVHs and DSHs are also available in the software package in order to pursue in‐depth evaluation of treatment plans and the analysis of treatment outcomes. It also offers a simple TPI evaluation option and a flexible POA module. The software is freely available by contacting the author. Future work includes developing additional features for multidimensional histogram analysis , other advanced plan evaluation tools, and statistical analysis modules with clinical relevance.HART is a user‐friendly, efficient, and precise DVH analysis software package built in a MATLAB environment. At present, it is also capable of importing AAPM/RTOG format files from the This work was supported by the research grant entitled “Oropharyngeal Function after Radiotherapy with IMRT” from National Institute of Health / National Institute on Deafness and Other Communication Disorders (NIH/NIDCD), USA (No. RO1DC007659‐01A1).Supplementary Material FilesClick here for additional data file.


Emerging quality of life data are expected to shed further light on the overall benefit of chemotherapy in women with advanced ovarian cancer in general, and on taxane−platinum combinations in particular.The taxanes paclitaxel and docetaxel show good activity in the management of advanced ovarian cancer when used in conjunction with platinum agents. Accumulating evidence from clinical studies, particularly the latest results from the phase III comparative SCOTROC study, indicates that the two drugs confer similar rates of tumour response and survival in women with this condition. However, it is clear that paclitaxel and docetaxel differ in their tolerability profiles and in other respects, and cannot be regarded as directly equivalent drugs. In particular, paclitaxel is associated with significant neurotoxicity; peripheral neuropathy has also been reported with docetaxel, but to a lesser extent. Neutropenia appears more prevalent with docetaxel than with paclitaxel, although clinical trial data show that this adverse effect is manageable and need not compromise dose delivery. Docetaxel is also associated with potential benefits accruing from shorter infusion times and lack of need for premedication with intravenous histamine H Despite advances in diagnostic techniques and therapy, cancer of the ovary kills more women than any other tumour of the reproductive system and therefore remains the gynaecological malignancy of greatest concern in industrialised countries . Only a The place of paclitaxel in the treatment of advanced ovarian cancer is well established, but a newer member of the taxane group, docetaxel, has been developed more recently. Docetaxel differs from paclitaxel in a number of respects and represents an alternative taxane with considerable promise and potential tolerability advantages in the management of ovarian cancer . In caseCurrent data suggest that the taxanes paclitaxel and docetaxel have similar efficacy, but regimens based on either of these two drugs have shown potentially important differences in their toxicity profiles. As it is always important to balance risks and benefits when setting out treatment plans for individual patients, knowledge of the tolerability differences between the taxanes available is clearly necessary for informed treatment decisions to be made. As part of this debate, this article reviews the toxicity profiles of each taxane and discusses QoL issues affecting patients with ovarian cancer.The clinical benefit in terms of median overall and progression-free survival of combining paclitaxel rather than an alkylating agent with a platinum compound in stage III–IV  of 5–6 mg ml−1 min−1 have subsequently been confirmed in a series of three phase II studies in a total of 66 patients  when carboplatin is used in place of cisplatin as a taxane partner has prompted researchers to explore combinations of docetaxel and carboplatin. A feasibility study of first-line therapy in 139 patients treated with a range of combination dosages of carboplatin plus docetaxel yielded an overall response rate of 66% and median progression-free survival of 16.6 months, with extremely low levels of neurotoxicity   of whom four withdrew from the study.A phase II trial from Japan has evaluated weekly paclitaxel 80 mg m1 and H2 antagonists in addition to oral corticosteroids before 1-, 3- or 24-h infusions, although there is some evidence that premedication is not needed before prolonged infusions (those exceeding 96 h). By contrast, the premedication regimen recommended for patients receiving docetaxel consists of 3 days' oral dexamethasone (8 mg twice daily).Patients receiving taxane therapy require premedication to minimise the risk of hypersensitivity reactions. However, the premedication guidelines recommended for paclitaxel and docetaxel are markedly different  in 75.4% of patients; the corresponding rate with paclitaxel (135–300 mg m−2 over 24 h) is reported to be 52%  plus carboplatin to AUC 5 with paclitaxel (175 mg m−2 over 3 h) plus carboplatin  supported these findings by showing a significant difference between the two treatments in tolerability profiles (vs 55%), although this was reported by the authors not to have compromised dose delivery or patient safety. As already discussed, guidelines are in place to aid clinicians in the use of colony-stimulating factors in patients likely to be at risk of myelosuppression, and appropriate treatment of this type would be expected to minimise the incidence and severity of neutropenia in patients receiving docetaxel with carboplatin in future studies.Grade IV neutropenia was reported in 75% of 139 patients with stage Ic–IV ovarian cancer who received 3-weekly docetaxel 60–85 mg mprofiles . A higheOf additional interest in this respect are the observations (reported earlier) of −2 or after multiple doses of 135–200 mg m−2. Patients who have received previous treatment with neurotoxic drugs appear in particular to be predisposed to this reaction. The neuropathy typically manifests initially as a burning or tingling sensation in the glove and stocking areas, and can progress to motor weakness with continued administration of the drug , but in one study a 24-h infusion of paclitaxel 135 mg m−2 was given  compared with 31% in the cisplatin–paclitaxel arm (n=392) were affected by grade II–IV neurotoxicity.Concerns over the neurotoxicity of combinations of paclitaxel with carboplatin have been raised by several authors. Three key comparative trials of paclitaxel–cisplatin −2 every 3 weeks) and carboplatin (AUC 4–6) in a total of 189 patients with ovarian and other carcinomas both showed incidences of peripheral neuropathy  in the docetaxel–carboplatin and paclitaxel–carboplatin groups, respectively. Most recent results (P<0.001) and 6 (P<0.001) and 10 (P<0.005) months after randomisation. Arthralgia and myalgia were also reported significantly less frequently by docetaxel than paclitaxel recipients  cancer include limitations of sexual activity, early menopause, chemotherapy-induced toxicity and loss of body image , together with the need for premedication with oral dexamethasone only, is likely to be more convenient and to reduce the stress placed on patients by their treatment relative to paclitaxel. Docetaxel—carboplatin has also been associated with reduced frequency and severity of neurotoxicity relative to paclitaxel/carboplatin in clinical studies in patients with ovarian cancer. Higher incidences of neutropenia have been reported in patients receiving the docetaxel combination, but this is reported to be easily managed and is not associated with increases in rates of treatment discontinuation or death.There are currently few data relevant to QoL in patients receiving taxane–platinum combinations for ovarian cancer, and QoL instruments cannot measure directly chemotherapy-related adverse effects. Nevertheless, the need for meaningful QoL assessments and the subsequent implications for treatment plans have become clear over the past decade, and results gained with the instruments available in comparative trials are awaited with interest. Familiarity of clinicians with differences between regimens in terms of toxicity, dosage and administration and QoL issues as data emerge and accumulate will assist in the optimisation of treatment decisions in patients with ovarian cancer.


Upper tract urothelial carcinoma (UTUC) of the kidney and ureter is arare neoplasm with roughly 3000 cases diagnosed in the United States in 2007,compared to approximately 67000 cases of bladder cancer. UTUC accounts for approximately 10% of cancersarising from the kidney and less than 5% of all urothelial malignancies. Predominantly due to the rarity of the disease, there isonly limited data to guide cliniciansin decision making which consists mostly of small retrospective studies andexpert opinion. As such, this special issue of Advances in Urology “ComprehensiveManagement of Upper Tract Urothelial Carcinoma” focuses both on controversiesin management as well as practical issues in the care of patients with UTUC. Asthe Guest Editor, my goal has been to ask a series of questions and seek answersfrom international experts in the field.The first practical matter is to address when endoscopic management ofUTUC is appropriate? Our first article “Endoscopic Management of UpperTract Urothelial Carcinoma” by Katie Moore et al. addresses this issue generally. Then, the paper entitled “EndourologicManagement of Upper Tract Transitional Cell Carcinoma Following Cystectomy andUrinary Diversion” by Jeffrey John Tomaszewski et al. tackles the difficult situation of UTUC after radical cystectomy andurinary diversion. Finally, after initial endoscopic management of UTUC, whatis the role of upper tract topical chemotherapy or BCG? This topic is thesubject of the paper entitled “Review of Topical Treatment of UpperTract Urothelial Carcinoma” by Kenneth G. Nepple et al.The next issue of focusis the clinical scenario when UTUC cannot be managed endoscopically. Arelaparoscopic and open nephroureterectomy equivalent operations? What is thebest way to handle the distal ureter and bladder cuff? These challenging topicsare addressed by a series of articles: “Laparoscopic Nephroureterectomy:Oncologic Outcomes and Management of Distal Ureter: Review of the Literature”by Andre Berger and Amr Fergany, “Laparoscopic Nephroureterectomy: The Distal Ureteral Dilemma”by Shalom Srirangam et al., as well as “Laparoscopic Nephroureterectomy andManagement of the Distal Ureter: A Review of Current Techniques and Outcomes”by Davis Viprakasit et al. Regardless of open versus laparoscopic approaches tonephroureterectomy, what is the role and extent of lymphadenectomy in themanagement of UTUC? This critical issue is dealt with in the paper entitled “RetroperitonealLymph Nodes in Transitional Cell Carcinoma of the Kidney and Ureter” byShilajit D. Kundu and Scott E. Eggener.The last matter is the managementof patients with locally advanced or metastatic UTUC. Is there a role foradjuvant chemotherapy? What are the best agents for metastatic UTUC? Can datafrom bladder cancer be applied to the upper tracts? These timely topics areconcentrated upon in the article “The Role of Chemotherapy in Upper TractUrothelial Carcinoma” by Peter H ODonnell and Walter M. Stadler. Finally, thesevarious issues are brought together and placed into perspective in the review entitled“Comprehensive Management of Upper Tract Urothelial Carcinoma” by GeorgiosKoukourakis et al.It has been my privilege to serve as the GuestEditor for this special issue of Advances in Urology “Comprehensive Managementof Upper Tract Urothelial Carcinoma.”Norm D. Smith


To assess risk for human exposure to avian influenza viruses (AIV), we sampled California wild birds and marine mammals during October 2005–August 2007and estimated human–wildlife contact. Waterfowl hunters were 8 times more likely to have contact with AIV-infected wildlife than were persons with casual or occupational exposures (p<0.0001). The emergence of highly pathogenic avian influenza virus (AIV) (H5N1) in domestic poultry in Asia with spillover infections in humans has raised concerns about the potential for a human pandemic  casual , 2) recreational (waterfowl hunters), and 3) occupational . Frequency of contact with AIV was estimated for each risk group by evaluating the prevalence of AIV among animals sampled opportunistically in each category. Surveillance for AIV was conducted from October 2005 through August 2007.For casual contact, wild bird species  were sampled to reflect typical daily exposures for the public . For recThe prevalence of AIV in each group was low (ranged 0.1%–0.9%) , and no We did not detect AIV (H5N1) in California during October 2005–August 2007 nor did other surveillance efforts in the United States (Novel transmission pathways are possible in places like wildlife hospitals because wild species that do not meet in nature are brought into close and extended contact with each other and humans. For example, marine mammals are susceptible to infection with AIV (We assessed the risk for human exposure to AIV by opportunistically sampling wildlife at the human–wild animal interface. A better measure of human risk would be to directly assess human exposure by testing for antibodies to all AIV subtypes that could occur in nature. Although it is not practical to simultaneously test for 144 virus subtypes, 2 serologic studies of persons exposed to wildlife showed antibodies to a limited number of AIVs (Although our methods enabled us to compare exposure risk among different groups, the testing methods we used likely did not estimate the true AIV prevalence in wildlife. The real-time RT-PCR used in this study and in national surveillance efforts (


Sir,−1 for 4 weeks on and 2 weeks off regardless of the differences in pharmacokinetic behaviour between individuals, it may be expected that some patients tolerate higher doses, whereas others need dose reduction (in vitro (We thank Dr Rezaei Kalantari for his interest in our study. Dr Rezaei Kalantari describes two patients with side effects requiring dose reduction of sunitinib, but who appeared to have developed an improved tolerance to sunitinib after re-escalation of the dose. As the dosing schedule of sunitinib is fixed as 50 mg dayeduction . The par


American Journal of Respiratory and Critical Care Medicine, researchers from the University of Southern California report that several inherited glutathione S−transferase (GST) gene variants were associated with lung function growth during adolescence, and one variant helped predict poor lung function in children whose mothers had smoked during pregnancy.Genetic research is beginning to provide potential insights on why some people are more vulnerable than others to various pollutants. Now a few more pieces can be added to the extraordinarily complex puzzle. In the April 2009 GSTMs. The best studied of these is GSTM1, which has been implicated in lung cancer, asthma, and other respiratory diseases in children and adults. To find out more about other variants, the authors looked at GSTM2, GSTM3, GSTM4, and GSTM5. They analyzed the genotypes in conjuction with eight years’ worth of lung function and genotyping data from 2,108 Southern California schoolchildren, starting around age 10 years.GST genes are expressed in the lungs, among other organs, and may influence the development of normal lung function. This study focused on a class of GST genes called GSTM2, two common haplotypes (patterns of genetic variation) were observed. One haplotype found in 28% of non−Hispanic whites and 44% of Hispanic whites was associated with better lung development than other haplotypes, whereas a second haplotype found in 35% of non−Hispanic whites and 30% of Hispanic whites was associated with significantly less lung function growth over time. Deficits in measures of lung function growth were twice as big in children with two copies of the haplotype versus those with one copy, and the deficits associated with this haplotype were greater among children of mothers who smoked during pregnancy.For GSTM4 haplotype found in 22% of non−Hispanic whites and 16% of Hispanic whites was associated with significantly reduced lung function growth relative to children with other haplotypes. As with the GSTM2 variant above, deficits in lung function growth were doubled among children with 2 copies of the haplotype. A GSTM3 haplotype found in about 7% of the children was associated with a deficit in one of three measures of lung function growth.The presence of a GSTM2 variants and prenatal tobacco smoke exposure on lung function growth. They noted that GSTM genes are expressed in fetal tissue at relatively low levels, and GSTs and other phase II (detoxification) enzymes are relatively inactive in fetal tissue compared with phase I enzymes (which activate toxic metabolites and carcinogens). “This suggests that fetuses are much more susceptible to environmental exposures than adults,” they wrote. “Genetic polymorphisms in phase II enzymes that further inhibit enzyme activity may exacerbate this susceptibility.” In addition, respiratory health and development in childhood is known to play an important role in adult respiratory health.The authors believe this to be the first study to report evidence of an interaction between GSTM−influenced failure to detoxify reactive oxygen species reduces lung protection and triggers an inflammatory cascade, bronchial constriction, and airway hyperresponsiveness, producing asthma−like symptoms and impaired lung development.This study “points out again that the genetic makeup of a population may be very important when considering health risks from environmental exposures,” says principal investigator Frank Gilliland, who directs the NIEHS−supported Southern California Environmental Health Sciences Center at the University of Southern California. His team speculates that However, more information would be needed before public health officials could set or adjust regulatory standards based on variation in vulnerability among subpopulations. And even with such additional data, Medea Imboden, a molecular epidemiologist at the University of Zürich, cautions against overemphasizing the GST gene family. “You always have doubts about the functional relevance of the variants,” says Imboden. “If you think of all the genes not yet known to contribute to respiratory health and bodily defense systems against air pollutants, GSTs might turn out to play a minor role.” But for now, she adds, “they are good candidates.”


Environ Health Perspect 118:259–264 (2010)].Scinicariello et al. have reported two text errors in their article “Modification by ALAD of the Association between Blood Lead and Blood Pressure in the U.S. Population: Results from the Third National Health and Nutrition Examination Survey” [First, in the third paragraph of their article (p. 259), the sentence summarizing results of a study of Korean lead smelter workers should have been as follows:n = 798; mean BLL = 32.0 μg/dL) found that the ALAD polymorphism did not change the association between blood lead and hypertension at occupational exposure levels compared with ALAD1 homozygous carriers .A study conducted among Korean lead smelter workers  was incorrect. The corrected sentence is as follows:ALAD, BLL, and BP—one conducted among occupationally exposed workers  and the other conducted at lower lead exposure level —found no association of ALAD polymorphism and BP outcomes.Two previous studies on The authors apologize for the errors.


What to do with crop residue left in fields at the end of a growing season is, literally, a burning issue. Some farmers prefer the inexpensive approach of setting the stubble ablaze, but repeated burning is not good for the soil,3Ravinder Agarwal, head of the University Science Instrumentation Centre at Thapar University in Patiala, India, and colleagues used portable spirometers to regularly test the lung function of children aged 10–13 and adults aged 20–35 over the course of a year. The 40 participants were healthy nonsmokers living in a village surrounded by farmland, with little traffic and no industry within 10 km.3Children’s force vital capacity (FVC)32.5 and PM10)—which make up the majority of the smoke produced by crop burning—were more closely associated with decreases in lung function than suspended particulate matter (SPM), which can contain particles 100 μm or larger.5Decreases in lung function correlated with increases in the concentration of particulate matter, which exceeded India’s national air quality standards during the burn season.The findings linking seasonal burning with health issues “coincide with the anecdotal evidence that we have been seeing in the Canadian prairies,” notes Kate Letkemann, environmental issues coordinator of The Lung Association, Manitoba, and a member of the provincial Crop Residue Burning Advisory Committee. On top of regulations regarding what time of day and where crop residue can be burned,710, and PM2.5,” notes Shijian Yang of the School of Environmental Science and Engineering at China’s Shanghai Jiao Tong University. But he would like to see further research that looks closely at the dose–effect relationship between lung function and crop residue burning. Yang’s work has shown that the peak concentration of PM10 and its duration may be more important than average concentrations for estimating the health effects of burning crops.8Argawal’s work “builds a relationship between pulmonary function tests and the concentration of SPM, PM


EHP 118(10):1444–1449; Chevrier et al.]. The findings may have implications for maternal health and fetal development.Polybrominated diphenyl ether (PBDE) flame retardants have been added to a wide variety of U.S. consumer goods including automobiles, airplanes, electronics, home furnishings, and furniture. Although two forms of PBDEs were phased out of use by 2004, data from the Centers for Disease Control and Prevention suggest exposure to these persistent, bioaccumulative, potentially toxic compounds remains widespread among the general U.S. population. New research now links higher exposure to PBDEs with reduced levels of thyroid-stimulating hormone (TSH) and higher rates of subclinical hyperthyroidism in women [Thyroid hormones are known to play an essential role in fetal brain development, and altered maternal thyroid hormone levels may adversely affect child neurodevelopment. The authors cite multiple animal studies showing that PBDEs alter pregnant rodents’ thyroid functioning. In the last year, laboratory tests using human cells suggested that PBDEs may affect brain development and linked the alterations to disruptions in thyroid hormone signaling. Recent research also has linked higher PBDE exposure to reduced intelligence in children.The authors believe their new study to be the largest to analyze associations between PBDEs and thyroid hormone during pregnancy. The 270 study participants were pregnant in 1999 and 2000 when they were recruited for the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. The research team measured the women’s thyroid hormone levels, then evaluated the data with models that adjusted for potential confounding factors, such as demographic characteristics and exposure to other persistent, bioaccumulative, and toxic compounds.4), suggesting subclinical hyperthyroidism. The combination of lower TSH and “normal” T4—as defined by the reference range applied to lab results—could mean an individual’s T4 levels actually are elevated above her body’s “set point”  of T4, which varies from person to person.Women with higher blood PBDE levels had lower levels of TSH. The women with the highest levels of PBDEs were more likely to have lower TSH but normal levels of the thyroid hormone thyroxine (T4. The only other study known to examine PDBEs and thyroid hormone specifically in pregnant women—which included only nine women—did not find increased T4, but the authors did not examine TSH levels. In contrast, other studies of pregnant women’s thyroid hormone levels have linked higher exposure to organochlorine pesticides and polychlorinated biphenyls—which have chemical structures and properties similar to those of PBDEs—with increased TSH and decreased T4.Most human studies in this area have associated increased exposure to PBDEs with elevated free T


Pregnant and breastfeeding women in high HIV‐incidence settings are at great risk for HIV‐acquisition and stand to benefit tremendously from HIV pre‐exposure prophylaxis (PrEP) scale‐up Mother‐infant pairs for this cross‐sectional study were identified at routine 6‐week postnatal check‐ups at which time data on the antecedent outcomes of birth weight and gestational age were abstracted from routine care records. Comparisons were made between pregnancy PrEP‐exposed and PrEP‐unexposed infants for the birth outcomes of preterm birth and low birth weight. Due to the uniqueness of the neonatal period, in which morbidity and mortality is higher than any other period of life, this participant selection strategy risks biasing the study sample to a lower‐risk group of infants who were alive and well enough to present to a routine care visit 6‐weeks after birth and thus less likely to have experienced the adverse birth outcomes of interest a priori, and perhaps establishing consensus amongst stakeholders, of what the acceptable margin of equivalence in birth and infant outcomes between PrEP‐exposed and PrEP‐unexposed pregnancies is, to avoid concluding there is no difference based on insufficiently sized studies with imprecise estimates and wide confidence intervals With anticipated wide‐scale PrEP uptake by millions of otherwise healthy pregnant women without HIV, the acceptable threshold for PrEP‐related adverse effects is likely lower among pregnant women without HIV than among those with HIV who are taking antiretroviral therapy for their own health with the additional substantial benefit of perinatal HIV transmission prevention. Going forward if the question in relation to PrEP safety in pregnancy is whether outcomes are equivalent between PrEP‐exposed and PrEP‐unexposed pregnancies, then future studies should be designed and powered as equivalence or non‐inferiority studies. This requires careful thought Considering the potential scale of pregnancy PrEP exposure to come in HIV high burden countries, strong evidence of the safety of PrEP during pregnancy is required. This includes from randomized trials powered to determine equivalence in outcomes and avoid biases inherent in retrospective observational or programmatic evaluations, in combination with carefully considered programmatic evaluations that appreciate the uniqueness of the perinatal period and can provide real‐world evidence for the safety of PrEP during pregnancy. As a global community, being prepared to scale‐up PrEP includes being prepared to provide quality evidence of the safety of PrEP in pregnant women and their PrEP‐exposed children.The author has no competing interests.ALS conceived of and wrote the letter.


ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.Autism spectrum disorder (A narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.Genome‐wide linkages, association studies, and genetic analyses of patients with ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.This review describes the genetic aspects of  In 1943Genetic causes of ASD were first identified by epidemiological studies of human populations diagnosed with autism  in patients with ASD suggested that proteins involved in synapse formation and synaptic transmission play an important role in the etiology of ASD , as well as proteins involved in synaptic structure, gene transcription, and chromatin remodeling , indicating that altered synaptic plasticity and regulation of gene expression may also be involved in the etiology of ASD ‐binding protein and variations in this gene have been linked to patients with ASD and intellectual disability  techniques are very efficient tools for the identification of novel candidate genes associated with ASD. Most of the studies have been performed on sporadic cases of ASD. Using NGS, O'Rack et al. identified de novo variations in Kalkman, . FinallyThese approaches have also identified variants in genes encoding ion channels. Here, we describe these variations and highlight the role of ion channels in ASD.2.22.2.12+ channels are present in many different cell types and they mediate Ca2+ influx in response to stimuli which can be a response to (i) change in the membrane depolarization; known as voltage‐gated channels or (ii) to a ligand‐mediated activation , inositol triphosphate receptor (IP3R) in the reticulum). In the brain, the elevation of intracellular Ca2+ concentration activates several signaling pathways that regulate important neuronal functions such as synaptogenesis, neuronal differentiation, and cell migration  and low‐voltage‐activated channels (LVA). HVA include L‐type, the neuronal N‐, P/Q‐, and R‐type. The low‐voltage‐activated Ca2+ currents are represented by T‐type channels. HVA are composed by a principal transmembrane subunit α1 (Cav α) associated with a disulfide‐linked α2δ (Cav α2δ) dimer, an intracellular β subunit (Cav β), and a transmembrane γ subunit (Cav γ), while LVA channels are composed only by α1 subunit. Both of HVA and LVA channels control the passive flow of Ca2+ across membranes. Therefore, alteration in their components leads to defective channel function that translates themselves into a variety of neurological disorders including hemiplegic migraine, episodic and spinocerebellar ataxia, epilepsy, and ASD , affecting exon 8 of the Cav1.2 channel α1 subunit gene (CACNA1C), have been associated with TS. They impair the Cav1.2 inactivation and lead to prolonged channel opening and consequent increase in Ca2+ flux  and myocyte enhancer factor 2  transmission and influencing neuronal firing. In fact, mice with dysfunctional CACNA1C show defects in N‐methyl‐d‐aspartate (NMDA) receptor activity leading to an NMDA‐independent long‐term potentiation in the CA1 region of the hippocampus that produces an acute decline in memory. These observations indicate that CACNA1C may play a role in NMDA receptor‐dependent signaling and in synaptic plasticity in the hippocampus. In addition to ASD, SNPs in CACNA1C gene are linked to psychiatric disorders including schizophrenia and bipolar disorder  and its regulatory β2 subunit (CACNB2) were strongly linked to psychiatric disorders and ASD  is a channelopathy described to be associated with ASD. TS is a multisystem disorder characterized by autistic features, cardiac abnormalities (QT prolongation), defective immune response, and syndactyly  were identified in families with ASD  was detected in two ASD‐affected individuals  of L‐type channels plays an important role in neuronal signaling and in brain function including memory and behavior  were identified in a cohort of patients affected with autism along with intellectual disability . Functional analysis of this variation performed in tsA‐201 cells demonstrated that it affects channel kinetics causing the inactivation of the Ca2+ current  mapped at 17q11–q21 region was found to contain SNPs  in patients with ASD  has been found, hampering the exploration of novel cellular pathways.The importance of defective regulation of intracellular Ca2.2.2+ channels are located in membranes of excitable and non‐excitable cells and they assure K efflux out of cells. According to their structure and functions, K+ channels are segregated into four categories: the voltage‐gated channels, inwardly rectifying (Kir), tandem pore domain (K2P), and the ligand‐gated (Kligand) channels  are ligand‐gated K+ channels that participate to several cell functions such as the regulation of hormone and neurotransmitter releases  in patients with ASD. Electrophysiological experiments on lymphoblastoid cell lines derived from patients with ASD manifested a reduced activity of these channels. The authors also found a missense variation that alters a conserved domain of the channel in one patient with ASD  has been implicated in generalized epilepsy and paroxysmal dyskinesia  leading to significant depolarizing shifts in the voltage dependence of activation and inactivation of the channel  was classified as one of the three predictive genes in ASD as it was strongly associated with SNPs‐ASD‐associated in a large meta‐analysis study  are essential for the initiation and propagation of action potentials in neuronal cells, muscles, and heart tissues. NaV channels are heteromeric complexes comprised of an α subunit (pore‐forming) associated with one or more β regulatory subunits. We distinguish nine members of NaV channels (NaV1.1 to NaV1.9) that differ by their structure but also by their ligand‐specific binding sites  which has led to their classification as critical drug targets  that occurs at exon 4 of SCNA2A gene generates a truncated protein , which alters a conserved residue of the channel. The biophysical consequences of this variation are an increase in Na+ current and partial channel inactivation  on chromosome 2  proteins anchored into the plasma membrane. Their roles are to couple the transport of Na+, K+, and Cl− and are named Na/K‐Cl  transporters. There are four different K‐CCCs . In neurons, NKCC1 and KCC2 are the predominant Cl− exchangers  and GABAergic  neurotransmission, neuronal connection  and ion permeability , as well as proteins directly involved in synapse formation such as neurexins (NRXNs) and neuroligins (NLGNs). Among the scaffold proteins, there are proteins involved in the regulation of cell adhesion molecules and neurotransmitter receptors density in the synapse. This is the example of SHANK family proteins that assemble into large molecular platforms interacting with glutamate receptors, ion channels, actin cytoskeleton‐associated proteins, and G protein‐coupled signaling pathways  binds to FMRP protein, the complex inhibits directly the translation of mRNA or indirectly by preventing the ribosomal translocation on mRNA. It is interesting to note that the expression of FMRP is under the control of Ca2+/calmodulin‐dependent protein kinase 4 (CAMKIV). However, CYFIP1 and CAMKIV have been described as susceptibility genes in ASD and together combined with an altered activity of FMPR enhances the ASD risk  or in neurons by the brain‐derived neurotrophic factor (BDNF) through the phosphoinositide‐3‐kinase (PI3K) activation the protein kinase B (Akt) and Ras to the extracellular signal‐regulated kinase  pathway also known as the mechanistic target of rapamycin kinase. via GAP protein through a mechanism that remains unknown  by phosphorylating TSC2 inducing its dissociation of TSC1. TSC1 and TSC2 proteins act like GTPase proteins and downregulate a small GTPase Rheb (Ras homolog enriched in brain) protein TSC1 and TSC2 genes have been associated with ASD  is coupled to an increase in AMPA receptors expressed at the synapse  used in the treatment of neuropathic pain  showed neuroprotective activity in experimental spinal cord injury studies, in neurobehavioral studies and tissue recovery  is one of the most widely used anti‐epileptic drugs for the treatment of tonico‐clonic seizures that act by modulating NaLoscher, . VPA is Loscher, . StudiesLoscher, . In factLoscher, . A recenLoscher, . In addiN‐methyl‐d‐aspartate receptors (NMDAR) are well known to be associated with psychiatric disorders  as a leading risk factor for ASD. Alterations of these channels highlight the complexity of the pathology that remains not fully understood. Interestingly, the wide implication of ion channels encoding genes in ASD may provide opportunities for pharmacological treatments of autistic patients because these channels represent powerful drug target. For instance, bumetanide is one of these potential therapeutic agents currently under evaluation. Some of ASD pathological conditions show an increase or decrease in ion channel activation/deactivation kinetics, suggesting that ion channel modulators may be therapeutic candidates for the treatment of ASD.A number of genetic studies came to classify autism as the most genetically complex disease. However, only a few numbers of contributing alleles or co‐inherited alleles are found in ASD proving that additional epigenetic factors or environmental conditions may contribute to the clinical manifestation of this disorder. The several Mendelian pathologies associated with autism, for example, fragile X syndrome, provide the strongest argument highlighting the genetic basis of autism. These ASD‐associated pathologies are commonly confounded with autistic behaviors and therefore make it more difficult to carry out case studies that focus exclusively on ASD. The most promising genes identified so far include In conclusion, ASD is not a simple pathology and it is associated with a large spectrum of other diseases. Nevertheless, the genetic abnormalities so far indicate that defective neuronal function from the onset of neural development appears to be a leading cause in the manifestation of this syndrome.Furthermore, defective regulation of ion flux through the cell membrane caused by altered kinetics of ion channels and transporters appears to cause an imbalance of excitation/inhibition in neural function that may lead to defective neuronal circuit formation and physiological response. Restoring ion dynamics to their physiological equilibrium may represent a promising therapeutic strategy for this devastating neurodevelopmental psychiatric disorder.All authors state that they have no conflict of interests.


Over the past decades, there has been an increasing understanding of cellular and molecular mechanisms that mediate modulation of the immune system by the autonomic nervous system. The discovery that vagal nerve stimulation (VNS) attenuates endotoxin‐induced experimental sepsis paved the way for further studies investigating neuro‐immune interaction. In particular, great attention is now given to intestinal macrophages: several studies report the existence of both intrinsic and extrinsic neural mechanisms by which intestinal immune homoeostasis can be regulated in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. Given the important role of inflammation in numerous disease processes, such as inflammatory bowel disease (IBD), cholinergic anti‐inflammatory mechanisms are under intense investigation both from a basic and clinical science perspective in immune‐mediated diseases such as IBD. This review discusses recent insights on the cross‐talk between enteric neurons and the immune system, especially focusing on macrophages, and provides an overview of basic and translational aspects of the cholinergic anti‐inflammatory response as therapeutic alternative to reinstall immune homoeostasis in intestinal chronic inflammation. Disruption of normal mucosal immune homoeostasis can potentially lead to uncontrolled chronic inflammation, such as that observed in inflammatory bowel disease (IBD). IBD is characterized by chronic inflammation of the intestinal mucosa with Crohn's disease (CD) and ulcerative colitis (UC) as the two main clinical presentations.Given the fact that intestinal Mφ are considered to be the main players in establishing and maintaining gut homoeostasis, loss of tolerance towards commensal bacteria or food antigens is believed to underlie chronic inflammation observed in IBD. Recent preclinical evidence indeed supports an important role for LpMφ in colitis. During inflammatory conditions, ie dextran sulphate sodium (DSS) colitis and T‐cell transfer colitis, there is a marked influx of monocytes and immature Mφ into the mucosal compartment through CC‐chemokine ligand (CCL)2 or MCP‐1 mediated recruitment2In the last decades, the implication of the autonomic nervous system (ANS), and specifically of the parasympathetic innervation, as a key player in immune homoeostasis has increased exponentially. This coincides with the publication of the seminal work by the group of Tracey, which in 2000 showed that the vagus nerve exerts a pivotal anti‐inflammatory input to the immune system, in particular to macrophages, also referred to as the cholinergic anti‐inflammatory pathway (CAIP)3Campylobacter jejuni infectionC. jejuni induces the expression of c‐Fos, an indirect marker of neuronal activity, in vagal sensory neurons and in the vagal primary relay nucleus in the brainstem. Similarly, the same c‐Fos induction was observed in the NTS in response to intestinal inflammation caused by surgical manipulation of the gut.muscularis externa, and improves the recovery of GI transit in a murine model of post‐operative ileus.The intestinal tract is densely innervated by the vagus nerve. Using anterograde tracers injected into the dorsal motor nucleus of the vagus (DMV), efferent vagal nerve terminals were shown to directly synapse with postganglionic neurons located in the ENS, rather than interacting with neurons in the prevertebral ganglia.44.1Autonomic dysfunction with a shift towards increased sympathetic tone and decreased vagal tone has been correlated with a higher risk for the development of chronic inflammatory disorders. Indeed, patients suffering from IBD often present impaired parasympathetic function , leading to sympathetic dominance,The activity level of the vago‐sympathetic balance and HPA axis can be assessed by peripheral measurements such as the heart rate variability (HRV) and serum cortisol levels respectively. The autonomic functioning can be studied in humans using HRV, a non‐invasive and quantitative electrocardiography‐based technique. Several studies have shown its predictive value in the prognosis of certain chronic inflammatory disorders including rheumatoid arthritis and IBD.4.2Animal studies have confirmed that autonomic imbalance contributes to the inflammatory exacerbation of experimental colitis Table . Of inteop/op mice did not develop a more severe colitis, highlighting a crucial role for Mφ in the CAIP.Moreover, adoptive transfer of Mφ from vagotomized mice into Mφ colony‐stimulating factor (M‐CSF) 1 deficient mice exacerbated the severity of colitis, suggesting a central role of Mφ in the vagal anti‐inflammatory effect.55.1The concept of central activation of the CAIP, either pharmacologically or using VNS, has become very appealing and might be a promising new approach in the treatment of IBD. Up to date, several preclinical studies have provided plenty of evidence supporting a beneficial effect of activation of the CAIP in a variety of disorders. It is indeed of great interest to translate this knowledge into improved clinical management of immune‐mediated inflammatory disease.+ cells.The role of ACh in the CAIP is undoubtedly proven: in the spleen, neural release of noradrenaline stimulates ACh release from memory T cells. ACh then, through binding of the α7nAChR expressed by Mϕ, inhibits the release of TNFα from splenic Mϕ thereby dampening inflammation. Therefore, increasing Ach release or prolonging its half‐life may mimic the anti‐inflammatory effect of VNS. In line with this background, several studies have investigated the effect of acetylcholinesterase (AChE) in preclinical models of colitis. AChE is involved in the termination of impulse transmission by rapid hydrolysis of ACh in numerous cholinergic pathways both in the central and peripheral nervous systems. Inactivation of this enzyme leads ACh accumulation and enhanced stimulation of nicotinic and muscarinic receptors. For example, galantamine (GAL) is a reversible, competitive AChE inhibitor, which crosses the blood‐brain barrier, increases brain cholinergic network activityIn addition, it was shown that the AChE inhibitors neostigmine and physostigmine were able to significantly attenuate macroscopic damage, influx of myeloperoxidase positive cells and smooth muscle thickness in a rodent DNBS model of colitis.+CD25− T cells via α7nAChR and NF‐kB signalling, an effect that was vagus nerve and splenic nerve dependent. Notably, this anti‐inflammatory effect was abrogated in splenectomized mice, suggesting that a possible vagus‐to‐spleen circuitry regulates intestinal inflammation.Central activation of the CAIP was also shown through the use of M1 muscarinic acetylcholine receptor (mAChR) agonist McN‐A‐343.−/− mice developed a more severe DSS‐induced colitis than their respective wild‐type littermates,−/− mice had a similar disease activity to their littermate controls. Conversely, treatment with  α7nACh receptor agonists  lowered DSS‐induced colon inflammation and improved clinical parameters of colitis,muscularis externa and the spleen.Interestingly, and in line with the early reports on VNS in sepsis, cholinergic modulation of MMφ by VNS was previously reported to be mediated by α7 nAChR in the small intestineTNFα and Il6 in intestinal monocytes and increased the expression of Arg1 in DDS colitis, contributing to improvement in disease activity score (unpublished results). Taken together, these data support VNS as potential novel approach to treat IBD.In addition to pharmacological activation of the CAIP, the VN can be stimulated by application of electrical pulses. Data on VNS in models of colitis are limited to rats, mainly because the electrodes for chronic VNS commercially available are too big in size to be applicable for implantation in mice. Meregnani et al provided initial preclinical evidence that chronic VNS has therapeutic potential in TNBS‐induced colitis. Using chronically implanted electrodes, electrical stimulation of the vagus nerve was performed 3 hours per day . This treatment alleviated the disease course of TNBS‐induced colitis, including weight loss, bleeding and diarrhoea, leading to remarkable decreases in the disease activity index (DAI) scores. This effect was mediated by inhibition of NF‐kB and mitogen‐activated protein kinase nuclear translocation.5.2After Tracey et al described the ability of VNS to improve survival in murine model of sepsis, the past 20 years have seen an exponential increase in interest in the therapeutic potential of VNS in immune‐mediated disorders. VNS has become an established FDA‐approved technique and is currently routinely used to treat drug‐resistant epilepsy and depression.Currently, only few data are available reporting on chronic VNS in patients suffering from IBD. A first attempt was described by Clarencon et al.Lately, the development of non‐invasive VNS techniques, ie approaches that do not require surgical implantation of an electrode and neurostimulator, are also becoming of interest. These techniques improve the safety and tolerance of VNS and are easy to use, making it more accessible for clinical use. One of these techniques involves transcutaneous activation of the vagus nerve via the auricular concha innervated by vagal afferents.Currently, two non‐invasive VNS devices are currently available on the market. NEMOS  is an external device that provides transcutaneous auricular VNS using an intra‐auricular electrode which stimulates the auricular branch of the VN. The second one, called GammaCore , is a non‐invasive VNS device currently being tested for headache, epilepsy and gastrointestinal disorders. It consists of two stainless steel discs that deliver a programmable number of stimulation cycles through a transcutaneous low voltage electrical signal to the cervical VN .Escherichia coli O:113) in a double‐blind placebo‐controlled trial.In humans, selective α7nAChR agonists are mostly being evaluated as potential treatments for schizophrenia and Alzheimer's disease. Only a limited number of clinical studies have determined their anti‐inflammatory potential. Of note, the selective α7nAChR agonist GTS‐21 attenuated cytokine production by LPS‐stimulated whole blood in healthy volunteers, and inhibited cytokine release in patients with severe sepsis more potently than nicotine.6The understanding of the pathogenesis of both CD and UC has considerably increased over the last years. To date, several studies have clarified the involvement of an aberrant immune response in these patients, where macrophages appear to be one of the key players in perpetuating chronic inflammation. Macrophages are specialized phagocytes with crucial roles in the maintenance of intestinal homoeostasis and motility. In the gut, Mφ are divided into different subpopulations depending on their location within the intestine layers and are tightly communicating with the microenvironment. Moreover, in the last decade, the ability of the intrinsic nervous system to modulate the immune response and the possibility to regulate it through VNS technique have obtained great interest.Current studies are focusing on developing non‐invasive VNS techniques to provide a safer and more durable therapeutics for IBD. Although preliminary data suggest that transcutaneous VNS to treat IBD could prove beneficial, further studies are warranted to better characterize VNS parameters needed to treat chronic inflammation.None. Click here for additional data file.


P and S wave scattering are often invoked as a source of extrinsic anisotropy, but our calculations show that they only generate minor seismic anisotropy . More generally, rock‐scale compositional layering, when present, cannot be detected with seismic anisotropy studies but mainly with wave scattering. In contrast, when grain‐scale layering is present, significant extrinsic anisotropy could exist in vertically limited levels of the mantle such as in a mid‐ocean ridge basalt‐rich lower transition zone or in the uppermost lower mantle where foliated basalts and pyrolites display up to 2–3% Vp and 3–6% Vs radial anisotropy. Thus, seismic anisotropy observed around the 660‐km discontinuity could be possibly related to grain‐scale shape‐preferred orientation. Extrinsic anisotropy can form also in a compositionally homogeneous mantle, where velocity variations associated with major phase transitions can generate up to 1% of positive radial anisotropy.Several theoretical studies indicate that a substantial fraction of the measured seismic anisotropy could be interpreted as extrinsic anisotropy associated with compositional layering in rocks, reducing the significance of strain‐induced intrinsic anisotropy. Here we quantify the potential contribution of grain‐scale and rock‐scale compositional anisotropy to the observations by (i) combining effective medium theories with realistic estimates of mineral isotropic elastic properties and (ii) measuring velocities of synthetic seismic waves propagating through modeled strain‐induced microstructures. It is shown that for typical mantle and oceanic crust subsolidus compositions, rock‐scale compositional layering does not generate any substantial extrinsic anisotropy (<1%) because of the limited contrast in isotropic elastic moduli among different rocks. Quasi‐laminated structures observed in subducting slabs using  Rock‐scale layering in the Earth's mantle produces negligible extrinsic anisotropyRock‐scale layering cannot be detected with seismic anisotropy but mainly with seismic wave scatteringGrain‐scale layering can generate substantial extrinsic anisotropy around the transition zone The former anisotropy is referred to as intrinsic mechanical anisotropy, while the latter is referred to as extrinsic mechanical anisotropy. Extrinsic anisotropy occurs when (i) the size of the SPO is much smaller than the wavelength of the seismic signal and (ii) the contrast in isotropic elastic properties between the compositional domains is very large. When these conditions are satisfied, seismology fails to distinguish a finely layered and strongly heterogeneous isotropic medium from a smooth intrinsic anisotropic medium Backus, .Within the Earth, extrinsic anisotropy can be related to either (1) the presence of a free gas or liquid phase included in elongated and preferentially oriented grain boundaries, pores, cracks, and porosity bands Crampin,  or (2) gRock‐scale compositional anisotropy has been traditionally invoked to explain part of the seismic anisotropy measured within the lithospheric mantle  and foliation  and rotation of grains due to the noncoaxial component of deformation. This type of SPO can be erased by postkinematic annealing.A further form of SPO may arise from stabilization of elongated rigid grains (porphyroclasts) floating in a viscous flowing matrix. This may either occur in simple shear or in a general noncoaxial flow depending on particle‐matrix coherence, strain vorticity, and particle aspect ratio  system by Newtonian viscous flow and as a function of the amount of shear deformation and of the imposed viscosity contrast  establishes. The strain within the matrix and the inclusions is equal to the bulk strain . The inclusions are perfectly aligned, and their shape is given by the bulk finite strain ellipsoid  and pyroxene  is less abundant  and majoritic garnet (60:40 for a pyrolitic composition). In dry conditions, garnet appears to be harder than any other abundant mineral phases of the upper mantle and transition zone , while majorite progressively transforms to Ca‐ and Mg‐perovskite and disappears at about 720–750 km . In dry eclogites, omphacite accommodates most of the deformation and garnet crystals behave essentially as rigid inclusions; in wet eclogite, the deformation is accommodated by shape change in both garnet and omphacite, yielding quasi‐laminated fabrics  dissolution processes, including recrystallization and solid‐state diffusion; the latter process is efficient for distances of few centimeters over hundreds of million years , while S waves  with the direction of polarization and propagation, respectively.3.1We compute the elastic tensors of perfectly layered media displaying grain‐scale and rock‐sale SPO using the Smooth Transversely Isotropic Long‐Wavelength Equivalent effective medium theory Backus, . We assuRadial anisotropy associated with grain‐scale layering  in pyrolite, harzburgite, and mid‐ocean ridge basalt (MORB) is shown in Figure  Hirose, . In harzS wave traveling from the base to the top of the mantle, such as core‐refracted SKS phases, would accumulate a maximum 0.4 s of splitting delay time.Radial anisotropy related to rock‐scale SPO in two‐phase mixtures with equal volume fraction of each component (yielding maximum anisotropy) is shown in Figure Long‐period body and surface waves are sensitive to a range of depth intervals rather than to a single layer as it was assumed so far. Hence, we have used gaussian curves as well as more realistic normal mode solutions of the wave equation  of harzburgite and MORB can produce up to 0.5–1% and 1–2% of radial anisotropy right above and below the transition zone, respectively. In a perfectly foliated pyrolite, grain‐scale SPO could be relevant in the uppermost lower mantle where the coexistence of majoritic garnet with bridgmanite results in These upper bound estimates are sensibly reduced in irregularly foliated/layered or nonlayered media, such that extrinsic anisotropy is minor when the solid heterogeneities are cylindrical and/or in the presence of a weak SPO. To which degree then are compositional heterogeneities laterally continuous and perfectly aligned within the convecting mantle?At the rock‐scale, the oceanic crust formed at intermediate‐ to fast‐spreading ridges certainly constitutes a distinct and laterally continuous layer in the oceanic lithosphere, while that formed at slow‐spreading ridges is rather irregular. Within the lithospheric mantle, geological data indicate that grain‐scale and rock‐scale compositional domains are not perfectly layered but can form anastomosed and lensoid patterns  could effectively generate significant extrinsic anisotropy given the large contrast in isotropic elastic moduli of the coexisting mineral phases. Presence of foliated fabrics in the garnet‐rich oceanic crust (forming when stishovite acts a weak inclusion) can locally produce high seismic anisotropy, provided the basalt volumetric fraction is high. Mantle convection simulations have demonstrated that density contrasts among the different rock components may favor mechanical unmixing and accumulation of MORB material in the transition zone (40–50%) as well as at the base of the lower mantle . Considering that most subducting slabs dip with a 30–60° angle, it follows that, even when the contrast in seismic velocities is large, the slab parallel quasi‐laminated structures would not affect significantly horizontally traveling surface waves. Similarly, SKS waves, which are mostly sensitive to the (receiver‐side) uppermost 500 km of the mantle , so that it is hard to distinguish mantle compositional layering in most if not all the mantle. The presence of “exotic” compositional heterogeneities such as sediments and serpentinites can produce significant extrinsic anisotropy because of the large contrasts in elastic moduli with dry mafic and ultramafic rocks, but the effect would be localized within and right above the subducting slab. It follows that rock‐scale compositional heterogeneities can be determined mainly from studies of P and S wave anisotropy measured in the intrinsically isotropic lower transition zone could be explained with grain‐scale SPO in MORB material accumulated above the 660‐km discontinuity. Thus, seismic anisotropy measured in these mantle regions could allow deciphering the strain‐induced grain‐scale SPO and hence the recent deformational history.In contrast, grain‐scale SPO, which is the expression of the recent deformation history, is a mechanism that potentially can produce detectable extrinsic seismic anisotropy. Large contrast in viscosity among the different phases of the aggregate will prevent the formation of planar fabrics due to the presence of elongated ribbons of the hard (matrix or inclusion) phase. Foliated pyrolitic‐harzburgitic mantle or basalts could explain the strength of the radial anisotropy measured in the uppermost lower mantle in between the postspinel and postgarnet phase transitions. The S wave finite‐frequency sensitivities and velocity variations associated with major phase transitions.Alternatively, we have shown that up to 1% of positive radial anisotropy can be generated in a compositionally homogeneous mantle around the transition zone boundaries due to Supporting Information S1Click here for additional data file.


The aim of this study was to estimate the cost‐effectiveness of interventional procedures alongside compression therapy A Markov decision analytical model was developed. The main outcome measures were quality‐adjusted life‐years (QALYs) and lifetime costs per patient, from the perspective of the UK National Health Service at 2015 prices. Resource use included the initial procedures, compression therapy, primary care and outpatient consultations. The interventional procedures included superficial venous surgery, endothermal ablation and ultrasound‐guided foam sclerotherapy (UGFS). The study population was patients with a chronic venous ulcer who were eligible for either compression therapy or an interventional procedure. Data were obtained from systematic review and meta‐analysis of RCTs.Surgery gained 0·112 (95 per cent c.i. −0·011 to 0·213) QALYs compared with compression therapy alone, with a difference in lifetime costs of €−1330 (−3570 to 1262). Given the expected savings in community care, the procedure would pay for itself within 4 years. There was insufficient evidence regarding endothermal ablation and UGFS to draw conclusions.This modelling study found surgery to be more effective and less costly than compression therapy alone. Further RCT evidence is required for both endothermal ablation and UGFS. Chronic venous hypertension is the most common cause of leg ulceration. The natural history is that of a continuous cycle of healing and breakdown of skin tissues over decades, causing considerable disability and impaired quality of lifeversus compression therapy have been conducted. Recent reviewset al.Compression with multilayer bandaging is standard therapy, with the aim of improving venous return and reducing venous hypertension until the ulcer has healed, followed by graduated compression stockings for life to prevent recurrenceversus compression therapy alone for treatment of chronic venous leg ulcers using a decision model. The primary (base case) study compared superficial venous surgery with compression. Scenario analyses incorporated the limited evidence from other interventional procedures, including EVLAThe aim of this study was to estimate the cost‐effectiveness of interventional procedures alongside compression therapy Analyses were performed from the perspective of the UK NHS and Personal Social Services at 2015–2016 prices. Currency conversion was made using purchasing power parities, at a rate of £1 = €1·088A Markov decision model was used to carry out the analyses. A decision model is a mathematical tool that links together the different types of evidence that might be of interest to decision‐makers in a coherent structure. In the context of venous leg ulcers, the relevant outcomes include the effectiveness of the treatments , the costs over the short and long term, and the impact of the treatments and the disease on health‐related quality of life (HRQoL). Clinical trials form the evidence base for such models, yet RCTs usually have follow‐up limited to a few years. As venous leg ulceration is a chronic condition, and can recur several times, a long decision horizon is appropriate. Decision models provide a framework for extrapolating outcomes beyond the trial reporting period.The population of this study was patients with a chronic venous leg ulcer who would be eligible for an interventional procedure or compression therapy alone. A chronic venous leg ulcer is defined as an open lesion between knee and ankle joint that has remained unhealed for at least 6 weeks and occurs in the presence of venous diseaseThe comparator was compression therapy alone. There are many variations of compression therapyFig. AppendixAppendix® . A copy is made available to researchers under a CC BY 4.0 licence (https://doi.org/10.17632/7634sv27zp.1).The two main effectiveness outcomes captured in the model are ulcer healing and recurrence. versus compression therapy. The systematic review included both observational studies and RCTs, but in the present study only results obtained from RCT data were included in the model, as the observational studies were assessed as of low methodological quality with a high risk of biasTableA clinical literature reviewThe evidence on EVLA was limited to a single RCTUGFS did not show more rapid healing than compression , although the trialFig. TableAppendixThe ESCHAR trialFig. AppendixThe ESCHAR trialThe ESCHAR trialTableNHS resources included two bandage changes per week  and both procedures resulted in reduced HRQoL at 1 week compared with baseline  index of 0·05; P = 0·024). In the model, it was assumed that the reduction in HRQoL was 0·05, lasting for 2 weeks after surgery and for 4 days after EVLA.Carradice and co‐workersThe results of the analyses were presented as estimates of mean total cost per patient and mean QALY for each therapy option. The following univariable sensitivity analyses were conducted to test the robustness of the results to alternative input data: no difference between surgery and compression in time to healing; no difference between surgery and compression in time to recurrence; an unhealed ulcer causes much higher detriment to HRQoL (utility 0·5); an unhealed ulcer causes little detriment to HRQoL (utility 0·9); only one bandage change per week; discount rate of 0 per cent and discount rate of 6 per cent per year.Appendixet al.Probabilistic sensitivity analyses were conducted using 1000 Monte Carlo simulationsTableFig. Fig. Fig. The results of the cost‐effectiveness model are shown in TableUnivariable sensitivity analyses alter one input to the model, leaving the others the same as the base case Table. In one TableThe probabilistic sensitivity analysis found that, using the base case inputs to the model, surgery had a probability in excess of 0·90 of being the most cost‐effective option at any cost‐effectiveness threshold. Analysis of co‐variance indicated that the RR for recurrence is the input parameter that explains most (over 86 per cent) of the overall uncertainty in incremental cost and incremental QALYs between surgery and compression therapy alone . The ESCHAR study found that 16 per cent of patients in the compression‐only group died and 19 per cent in the surgery group (P = 0·245), and the ulcer‐free time at 3 years was 100 weeks with surgery and 85 weeks with compression alone. The model predictions are not exactly the same as in the ESCHAR trial, because the model incorporates clinical risk evidence from diverse sources .It is important to validate a model by comparing predictions against observed data. The model predicted the death of 17 per cent of patients (the same in each treatment group), and the mean ulcer‐free time was 89 weeks in the surgery group versus interventional procedures  for the treatment of venous leg ulcers. The main finding was that surgery is the most effective and least costly treatment option. Venous leg ulcers are very costly for health services to treat and, by preventing recurrence, surgery would pay for itself within 4 years, compared with compression therapy alone. The results are robust to alternative assumptions. If the outcomes of the study by Viarengo and colleaguesThis study estimated the cost‐effectiveness of compression therapy alone This is the first cost‐effectiveness analysis to compare surgical procedures with compression therapy for venous leg ulcers. The data for RRs were based on a systematic review of RCTsIn some of the older RCTs, such as ESCHAR, many patients in the interventional arm either did not have surgery or underwent procedures that would be considered suboptimal by modern endovenous standardsOne common treatment modality not included in this study is endovenous RFA. This was owing to a lack of published randomized trials using RFA in patients with chronic venous ulcers. However, the mode of action and published technical success rates are comparable to those for EVLANo other cost‐effectiveness analyses have compared interventional procedures with compression therapy. VenUS I estimated the annual cost of compression therapy with multilayer bandaging to be €1412 (95 per cent c.i. 1291 to 1600)  at 2001 pricesFurther research would be worthwhile in several areas. First, the analysis indicated that the RR for recurrence is the most influential parameter in this decision. There may be different impacts by subgroups. ESCHAR found that the greatest relative benefit of surgery tended to be in patients with isolated superficial venous reflux. Further RCTs, or meta‐analysis of existing RCTs using individual patient data, might investigate whether differing patterns of venous reflux or other factors influence outcomes. Second, further RCTs should compare interventional procedures with one another as well as, or instead of, compression therapy. Endothermal procedures might be extremely effective for the treatment of venous leg ulcers, but this evidence is still weak. There is currently an ongoing RCT comparing early endovenous ablation  with delayed endovenous ablation for the treatment of venous leg ulcers (Early Venous Reflux Ablation (EVRA) trial; ISRCTN02335796). Once finalized, these results will inform the optimal use and timing of endovenous procedures in the management of leg ulcers.The results of this study should inform the next generation of clinical guidelines for venous leg ulcers. In a very challenging economic climate, the delivery of surgical procedures to patients with chronic venous ulcers would require significant changes to current pathways of care. These patients usually present to and are managed by community nursing teams in the very peripheries of healthcare systems, whereas surgery, specialist venous scanning and endovenous interventions are usually delivered in secondary care environments. Published guidelines should be supported by plans for implementation and robust audit frameworks.Appendix S1 Model structureAppendix S2 Weibull model for estimating rates of eventsAppendix S3 Probabilistic sensitivity analysisAppendix S4 Calculating probabilities from ratesTable A1 The transition rate matrix QTable A2 The transition rate matrix Q, simplified to exclude tunnel statesTable A3 Eigenvalues matrix DTable A4 Representation of matrix D using intermediate variablesTable A5 Exponential of DTable A6 Eigenvectors matrix UTable A7 Representation of matrix U using intermediate variablesTable A8 Inverse of U = U‐1Table A9 Probability matrix PTable A10 Probability matrix P, expressed in terms of intermediate variablesTable A11 Reconstituted 8x8 probability matrix with tunnel statesFig. S1 Incremental cost‐effectiveness ratio  over time. Difference in cost: difference in overall cost in euros per patient between surgery and compression therapy only. Dominates: the overall costs of surgery are lower and the health gain is greater than compression therapy aloneTable S1 Results of analysis of co‐varianceClick here for additional data file.