Evaluation of ventricles volume and maximum CSF pressure (before shunting) following results validation indicated that these parameters were the most proper hydrodynamic indices and the NCH type doesn’t have any significant effect on changes in two indices. The results confirmed an appropriate correlation between these indices although the correlation decreased slightly after the occurrence of disease. NCH raises the intensity of vortex and pulsatility (2.4 times) of CSF flow while the flow remains laminar. On day 18 after shunting, the CSF pressure decreased 81.0% and all clinical symptoms of patients vanished except for headache. Continuing this investigation during the treatment process showed that maximum CSF pressure is the most sensitive parameter to patients’ clinical symptoms. Maximum CSF pressure has decreased proportional to the level of decrease in clinical symptoms and has returned close to the pressure range in normal subjects faster than other parameters and simultaneous with disappearance of patients’ clinical symptoms (from day 81 after shunting). However, phase lag between flow rate and pressure gradient functions and the degree of CSF pulsatility haven’t returned to normal subjects’ conditions even 981 days after shunting and NCH has also caused a permanent volume change (of 20.1%) in ventricles. Therefore, patients have experienced a new healthy state in new hydrodynamic conditions after shunting and healing. Increase in patients’ intracranial compliance was predicted with a more accurate non-invasive method than previous experimental methods up to more than 981 days after shunting. The changes in hydrodynamic parameters along with clinical reports of patients can help to gain more insight into the pathophysiology of NCH patients. The production of cerebrospinal fluid (CSF) is the primary function of the choroid plexuses . Active The first group includes experimental studies on hydrocephalus patients during their treatment procedures which evaluate and compare CSF hydrodynamics during treatment process –9. Most The second group includes those studies which evaluate CSF flow using computer modeling. In this group, there are also studies using 2D computer simulations or studies with incomprehensive solution methods like finite element method or computational fluid dynamic for modeling hydrocephalus –17. TheySome studies compared the CSF flow among normal subjects and hydrocephalus patients (before treatment) using FSI simulations ,11,18. VEleven NCH patients who experienced no disruption in their shunt during treatment process were recruited. As no record of patients’ conditions before disease was available, 13 normal subjects of approximately the same sex, age, height and weight were selected in order to compare the deviation of patient conditions from normal status. Relevant information on NCH patients and normal subjects are listed in It is noteworthy that the number of recruited cases is regarded as one of the advantages of this study. In previous computer simulations, fewer numbers of cases comparing to the present study were recruited although they did not evaluate the treatment and healing process of patients with shunt surgery using FSI. Hence, the results of this study are more reliable.All procedures performed in studies involving human participants were in accordance with the ethical standards of North Tehran Branch, Islamic Azad University, Tehran, Iran,  and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Furthermore, this article does not contain any studies with animals performed by any of the authors.in vivo measurement of CSF flow. The velocity encoding value, repetition time, flip angle, echo time, field of view, slice thickness and matrix size were 100cm/s, 18msec, 23°, 8.3msec, 23cm, 3mm and 256x198, respectively. The details of this imaging protocol were provided in the previous study [The cine-PC MRI is considered as a tool for Fully coupled FSI simulations were performed and the arbitrary Lagrangian-Eulerian (ALE) equations were used for analyzing fluid and solid models. For iteration scheme, we used the full Newton–Raphson method. CSF circulating in the ventricles and SAS was considered as the fluid model while the brain tissue was considered as the solid model. Due to insignificance of skull deformation in hydrocephalus patients , the out3, respectively [F, W, P, Sf, ρF and F-W" in ALE represents the relative velocity of CSF regarding the moving coordinate velocity. Eqs s, σs and üS represent the brain density, Cauchy’s stress tensor of brain and the local acceleration of the solid part, respectively.Further, the CSF was assumed as an isothermal, incompressible Newtonian fluid. The dynamic viscosity and density of CSF equaled to 0.001 kg/ms and 1000 Kg/mectively ,13. The Previous studies have used various constitutive models to analyze the brain tissue in hydrocephalus patients. According to the study by Hrapko et al. the brain tissue should be analyzed with a time-dependent stress-strain model . Cheng eo represents instantaneous shear modulus.τk and The general equations were derived from the equation of the solid model, law of Darcy of fluid flow through a porous medium and the conditions of equilibrium of a stress field according to the study by Cheng et al. The additional parameters in a poro-viscoelastic model include the modulus of relaxation .The consThe CSF is produced mainly in lateral, third and fourth ventricles ,30. As tTwo locations were considered for CSF outlets in this simulation: the sagittal sinus and spinal cord ,30,32–36Similar to the inlet flow rate, the outlet flow rates of CSF were produced in MATLAB through superposing the diagrams of the normalized blood flow rate and the constant amplitude .The post-shunting results were obtained by adding one shunt with inner diameter of 1.3 mm in three-dimensional model of the patients’ right lateral ventricle and rerunning the models. The post-shunting boundary conditions were assumed similar to the pre-shunting conditions. Only the minimum and maximum values of the output pressure diagram in the shunt tube were considered 1422 and 1667 Pa, respectively. For more details about this pressure diagram see: Medtronic, Strata Various Adjustment System, Minnesota, USA.Grid and time-step independence studies were crucial to ensure the accurate solutions of the applied numerical simulations. A fully implicit Euler scheme was implemented in this study. The initial grid was refined using the maximum simulated velocity and pressure at two locations by a step-size of 0.01s . The maxStatistical parameters such as mean value, range, standard deviation (SD), coefficient of variation (CV)  and Pearson correlation coefficient (PCC) were calculated using SPSS version 20.The results of 3D FSI simulation were calculated for each case and for each phase (one phase pre-shunting and five phases post-shunting) in 4 working cycles. Since there is no difference between the results of cycles 3 and 4, only the results of the third cycle are reported in this section. It is however necessary to guarantee the accuracy of boundary conditions, the assumptions and problem-solving process before examining the results through data validation.To ensure the validity of results, the CSF velocity in AS of all normal subjects and patients (before shunting) and the intracranial pressure (ICP) in patients (before shunting) were measured experimentally and compared with the computer simulation results. To do so, the velocity diagram of CSF in AS obtained from cine-PC MRI was compared with the one calculated by FSI modeling in all normal subjects and patients . The reaThe maximum difference between the extremum (maximum or minimum) values of CSF velocity in AS measured by cine-PC MRI and CSF velocity calculated using FSI simulation for all cases was less than 3.8% while the maximum error in phase lag of these diagrams was less than 0.6% .To validate the CSF pressure results, the maximum ICP was measured in 11 patients (before shunting) using ICP monitoring. For this aim, a small opening was created in skull and in the dura and an ICP micro-sensor  was inserted 1–2 cm into the brain parenchyma; the sensor was zeroed before insertion against the atmospheric pressure . To obtaAs seen in In order to evaluate the conditions of hydrocephalus patients, the changes in the volume of head substructures should be emphasized . The meaThe precise examination of the details related to CSF velocity fields indicated irregular flow patterns in CSF flow. The results showed that the vortices were significantly weaker in normal subjects . TherefoBased on the results in The mean value of maximum CSF velocity value in AS was 6.20 ± 1.9 cm/s among the 11 patients while it was 3.92 ± 1.3 cm/s for the 13 normal subjects . The meaGenerally, the clinical symptoms of NCH are divided into two groups . First, The patients’ mean of maximum CSF pressure in the lateral ventricle, AS, BONS and the maximum ICP are 2853.6 ± 215.8, 2847.2 ± 215.6, 2856.5 ± 218.2 and 2866.5 ± 216.2 Pa, respectively . TherefoThe Womersley number was used to analyze the pulsatility of CSF flow. The Womersley number is regarded as a non-dimensional number derived from the unsteady Navier-Stokes equations and an expression of the pulsatile flow frequency in relation to viscous effects and is calculated by the following equation :α=R2πρfThe Womersley number was greater than 1 for all cases . The floThe CSF pressure diagrams of the NCH patient No. 1 before shunting and the normal subject No. 2 were compared with each other in two cross-sections of the AS and BONS . ContrarWomersley proved a phase lag between flow rate and pressure gradient functions . Fig 5b In the present study, the differences between CSF bio-fluid parameters in patients (before shunting) and normal subjects were compared first to find the proper hydrodynamic indices before shunting. Then, the conditions of three patients were followed up until 981 days after shunting, but evaluation of the changes in cellular response of NCH brain tissue was not the objective of this study.In this section, the conditions of patients (before shunting) and normal subjects are compared. First, it seems necessary to investigate and evaluate the data dispersion for each parameter statistically.The CV for the maximum CSF velocity of NCH patients was more than 30% while it was less than 7.6% and 6.5% for the maximum CSF pressure and ventricles volume of the same patients, respectively Tables  and 3. TThe PCC represents a measure for the relationship between two variables. The range of this coefficient is +1 to -1. The PCC between proper indices (maximum CSF pressure and the ventricles volume) was +0.91 (p<0.01) and +0.84 (p<0.01) for normal subjects and patients, respectively . PCC resBased on the results, the difference between proper indices in the three groups of patients  includinAll the aforementioned steps from MRI to meshing and analysis were repeated for new head models of NCH patients No.1-3 at five post-treatment stages within 5, 18, 81, 903 and 981 days after shunting. Unfortunately, follow-up of other patients was not possible.The maximum CSF pressure in both BONS and AS of NCH patient No.1 within 5, 18, 81, 903 and 981 days after shunting was about 48.0%, 81.0%, 81.9%, 81.9% and 81.9% less than the pre-shunting pressures, respectively . FurtherBased on report of the attending medical team, all clinical symptoms of the disease except for headache disappeared completely in all three patients within 18 days after shunting. The maximum CSF pressure in both BONS and AS returned to mean values of these pressures in normal subjects with a difference of merely 8.7~8.9%. For instance, NCH patients No. 1–3 and 7 experienced papilledema symptom before shunting  but thisOn day 81, the maximum pressure values in BONS and AS of NCH patient No.1 reduced to 590.6 Pa and 572.4 Pa, respectively. The ventricles volume was about 23.3% greater than the mean value of ventricles volume in normal subjects. The results of models analyses on day 81 showed that the values of Womersley number were almost constant with a difference of less than 1.6% comparing to day 18. Although pressure values reached very close to normal conditions and all the clinical symptoms vanished on day 81, the ventricles volumes and the flow pulsatility (Womersley number) had still a significant difference comparing to normal subjects’ conditions.On day 903, the ventricles volume among the patients decreased by about 3.2%  although the maximum pressures in BONS and AS were equal to the pressure values calculated on day 81. In other words, the CSF pressure reached a stable and constant state on day 81 after shunting while the ventricles volume reduction in patients continued on a slight slope. The value of Womersley number had no significant changes between days 81 and 903 after shunting. Further, no changes were observed in all examined parameters between days 903 and 981 after shunting. It is worth mentioning that the phase lags between the flow rate and pressure gradient functions had no changes from pre-shunting step up to 981 days after shunting.The important point is that even more then 2.5 years after shunting and complete healing of patients the numerical values of none of the examined parameters, except for pressure, returned to the ranges in normal subjects. For example, the results obtained for Womersley number showed that the average of this number after occurrence of NCH increased 2.4 times but the level of CSF flow pulsatility had no significant decrease (less than 6%) after complete healing of patients.Furthermore, NCH caused permanent volume changes in ventricular system and this volume change continued even 2.5 years after shunting. It can therefore be concluded that about 20.1% of the ventricles volume likely wouldn’t return to a normal state more than 2.5 years after shunting and healing. In other words, the amount of 20.1% can be equivalent to the concept of residual strain since this amount is related to the volume, which has not returned to mean value of ventricles volume in normal subjects even more than 2.5 years after unloading of brain tissue and ventricles through shunting.Despite the fact that clinical symptoms in patients disappeared on day 81 after shunting, NCH caused permanent changes in parameters such as ventricular volume, Womersley number and phase lag between flow rate and pressure gradients and shunt surgery and treatment process could not play any role in changes of these parameters. It can be deduced that despite of obvious difference in many of CSF bio-fluid parameters with respect to normal subjects, after shunting, patients have experienced a new healthy state in new hydrodynamic conditions different from normal conditions.Moreover, P-t and V-t views in In the present study, the white and gray matters were not considered separately in the brain tissue model. Of course, the brain tissue has been considered as a single part in many studies and there are also conflicts about the importance and necessity of modeling the brain in two parts. On the one hand, according to the study by Dutta-Roy et al., a single-part-model is also sufficient for modeling the brain in patients with normal pressure hydrocephalus . On the The changes in CSF biofluid parameters during shunt treatment process of NCH patients using computer simulation hasn’t been investigated in previous studies. In the present study, these effects and ICC diagram have been investigated using 3D FSI simulation up to 2.5 years after shunt surgery in a large number of NCH patients through a non-invasive method. Results indicated that the ventricles volume and maximum CSF pressure are more proper indices, than the velocity, for hydrodynamic assessment of NCH patients (before shunting). The type of hydrocephalus also played no significant role in changing these indices. Moreover, the intensity of vortex increased, the location of vortex formation changed and the CSF flow was 2.4 times more pulsatile after NCH occurrence while the CSF flow remained laminar. The results also indicated that all clinical symptoms, except headaches, disappeared on 18 day after shunting. The ventricles volume of patients on day 18, despite of the considerable pressure drop , was 1.5 times more than the mean value of ventricles volume in normal subjects. Although investigating the biofluid parameters before the beginning of treatment process showed that the maximum CSF pressure and ventricles volume are the most proper bio-fluid indices, continuing this investigation during the treatment process showed that maximum CSF pressure is the most sensitive and the most proper hydrodynamic parameter. Maximum CSF pressure has decreased significantly, proportional for the level of decrease in clinical symptoms, and it has returned to a level close to normal subjects’ conditions. It also returns close to the pressure range in normal subjects faster than other parameters and simultaneous with disappearance of patients’ clinical symptoms (from day 81 after shunting) and its value remains stable and constant state on day 81 after shunting. However, NCH has caused permanent changes in phase lag between flow rate and pressure gradient functions, Womersley number (the level of pulsatility of CSF flow) and ventricles volume  even 981 days after shunting and healing. Therefore, it can be deduced that patients have experienced a new healthy state in new hydrodynamic conditions after shunting and healing despite the fact that there are permanent changes in CSF biofluid parameters (except for pressure) and these parameters haven’t returned to normal subjects’ conditions. Finally, the manner ICC increases during the healing process of NCH has been presented in this study in a more precise way comparing to previous studies. The manner of changes in CSF biofluid parameters with regard to their clinical symptoms can reflect the complexity of CSF flow dynamics in NCH patients during healing process and can help physicians in quantitative assessment of NCH patients’ conditions and can also help to gain more insight into the pathophysiology of NCH patients.S1 AppendixThe Womersley numbers have been also plotted in the inferior section of third ventricle. SAS: subarachnoid space; BONS: behind optic nerve sheath; AS: aqueduct of Sylvius; LV: lateral ventricle; NS: normal subject.(DOCX)Click here for additional data file.


Assessment of nerve trunk mechanosensitivity using the upper limb neurodynamic test 1 (ULNT1) often includes measurement of the angle of occurrence in the range of pain onset (PO) and submaximal pain (SP). A measurement that better fits the idea of mechanosensitivity could be the angle between PO and SP (AbOS). This study investigated the intra- and intersession reliability of AbOS, PO, and SP during the ULNT1. Forty-four healthy volunteers underwent three ULNT1 to the point of PO and SP, twice in the first session and once in the second. AbOS, PO, and SP angles of occurrence reliability were examined using the Intraclass Correlation Coefficient  and Bland-Altman plots. The intra- and intersession ICC values for AbOS were 0.71  and 0.79 , respectively. The intra- and intersession mean difference and 95% limits of agreement (±1.96 SD) in the Bland-Altman plots were 2.3°  and 2.8° , respectively. The intra- and intersession reliability of the AbOS during the ULNT1 in healthy individuals is high and higher than the reliability of PO and SP angles of occurrence. The AbOS could be a preferable variable in the assessment of neural mechanosensitivity. Neurodynamic tests are common procedures used by physiotherapists treating patients with disorders involving musculoskeletal pain to assess nerve mechanosensitivity and test the involvement of neural structures as a possible source of pain –8. They The application of mechanical stress to peripheral nerves and nerve trunks by the ULNT1 can provoke pain and other sensory responses  , 19. HowAlmost all the criteria for mechanosensitivity assessment rely on subjective findings as referred by patients (pain occurrence) or determined by the examiners (resistance to movement). The only proposed method to quantify mechanosensitivity is joint angle measurement (e.g. “elbow extension” for the ULNT1) at the moment of PO and SP , 23, 24.This study on healthy participants aimed to investigate the intra- and intersession reliability of AbOS and to explore whether it was higher than the reliability of PO and SP angles of occurrence.All the experimental sessions were conducted between April and June 2013 in the Laboratories of Movement Analysis of the San Raffaele Hospital . Ethical Guidelines for Pain Research in Humans. All volunteers signed an informed consent form prior to the study. The proposed methodology was developed according to the Guidelines for Reporting Reliability and Agreement Studies [The procedures were conducted according to the Declaration of Helsinki. The study respected the Studies .A convenience sample of 44 healthy participants  was recruited from the students of the Bachelor in Physiotherapy Programme of the Vita-Salute San Raffaele Hospital University .The inclusion criteria were nonpainful full active range of motion (ROM) for bilateral shoulders, elbows, wrists, hands, and cervical spine. Exclusion criteria were current or recent (at least three consecutive days in the past six months) neck or upper extremity pain, nervous system disorders, diabetes mellitus, upper extremities, breast or cervical spine surgery, drug or alcohol abuse, and radiation therapy or chemotherapy in the past year. The sample size was set according to suggestions by Giraudeau and Mary  for the An electromagnetic tracking device  in combination with the custom-made goniometer software provided real-time visual feedback of gleno-humeral movement degrees Figures , which aULNT1 Procedure. ULNT1 was performed according to the description of Butler and Matheson [ “the moment when the least experience of pain was recognized” and SP as “the moment when pain or tingling increased and the subject wanted the test to cease.” Randomization of the side to test was initiated by asking the first participant to choose between two cards hidden in an envelope. The next participant was allocated in the opposite order and the same method was used for all subsequent participants. During the ULNT1 execution, gleno-humeral movements were not to exceed more than 10° (arbitrary set) of deviation from the starting position. If so, participants were excluded from the study. Participants were also excluded if SP was not elicited throughout the full available range of motion.Matheson , except Matheson , PO was Participants' Instruction and Experimental Set Up. A standard explanation of PO and SP definitions was given and a demonstration of the ULNT1 was performed on the nontested arm by the operator. Participants were instructed to stop the ULNT1 at PO and SP. They laid supine with legs straight and both hands on their belly. A soft, thin (4 cm) foam pad was positioned under the head to avoid discomfort. The brackets of the positioning device were placed over the acromion-clavicular joints, bilaterally, as shown in Data Acquisition. During each ULNT1 performance, participants indicated the occurrence of PO and SP by pressing the switch button and completed the VAS after SP was reached. The AbOS was calculated for each of the three ULTN1 performances. AbOS1, AbOS2, and AbOS3 corresponded to the angle measured during the first, second, and third ULNT1, respectively (ectively .α = 5%).Descriptive statistics were used to present data. The distribution of AbOS, PO, and SP occurrence and VAS values were tested using the Shapiro-Wilk's test  and Bland-Altman plots (B-A plots)  as recomThe ICC ranges from 0 to 1, with values closer to 1 representing the higher reliability and 1 meaning that “reliability is perfect” , 35. TheB-A plots (CI: 95% and limits of agreement set at ±1.96 standard deviations) were generated to provide the limits of agreement and the visual representation of the size and range of differences between two AbOS from the same participant. The same statistical analysis was performed to test the intra- and intersession reliability of the angles of occurrence of PO and SP and pain intensity at the moment of SP.p < 0.05.IBM® SPSS® Statistics 20.0.0  was used to run statistical analysis. Significance level was set to From the initial sample of 44 participants, two were excluded due to equipment failure (wi-fi connection failure between the hub and the G3 antenna) and 13 because the deviation of gleno-humeral movements exceeded 10° from the starting position. The final sample consisted of 29 participants.p < 0.05). The median and minimum and maximum values of AbOS1, AbOS2, and AbOS3 and the angles of occurrence of PO and SP, and VAS are presented in The measurements collected were not normally distributed, as assessed by the Shapiro-Wilk's test  and 0.79 , respectively. The mean difference AbOS1 − AbOS2 as calculated in the B-A plots was 2.3° and the 95% limits of agreement were −18.3° and 23.1°  and 0.64 , respectively. The mean difference PO1 − PO2 as calculated in the B-A plots was 2.5° and the 95% limits of agreement were −33.9° and 28.8°. The mean difference PO1 − PO3 was 5.3° and the 95% limits of agreement were −30.7° and 19.9°.SP Occurrence Angle. The ICC values for SP1_SP2 and for SP1_SP3 were 0.55  and 0.48 , respectively. The mean difference SP1 − SP2 as calculated in the B-A plots was −0.1° and the 95% limits of agreement were −26.8° and 26.5°. The mean difference SP1 − SP3 was −2.5° and the 95% limits of agreement were −29.2° and 24.1°.VAS Recorded at SP. The ICC values for VAS1_VAS2 and for VAS1_VAS3 were 0.92  and 0.87  respectively. The mean difference VAS1 − VAS2 as calculated in the B-A plots was −0.4° and the 95% limits of agreement were −2.0° and 1.1°. The mean difference VAS1 − VAS3 was −0.1° and the 95% limits of agreement were −2.0° and 1.7°.ICC and B-A plot values are reported in The intra- and intersession reliability of the angle between PO and SP during the ULNT1 was investigated. Furthermore, the intra- and intersession reliability of PO and SP occurrence in the range was tested. The results showed a “high level” of reliability for the first measurement and a “low level” of reliability for the latter ones.An experimental setting was chosen for this study. Custom devices for participants positioning and an electromagnetic goniometer were used to guarantee (as much as possible) an appropriate level of accuracy during ULNT1 performance and data acquisition. The time interval between two consecutive ULNT1 was set to 1 minute to maintain as stable as possible the participants' condition, as suggested in some recent studies with a similar experimental design , 41. ForThe angle between PO and SP measured during each ULNT1 performance corresponded to approximately 30°; this was different from other studies on healthy individuals where PO occurred 10° earlier in the range than SP , 23. A pThe ICC and B-A plots suggested a high level of reliability both for the intra- and the intersession reliability of the angle between PO and SP, with a slightly higher ICC and a smaller amplitude of B-A plot limits of agreement for the inter-session reliability. No previous data are available for this variable. Only Coppieters et al. , while eThe intrasession reliability of PO and SP occurrence in the range, as measured in this study, was substantially lower than in results of previous research that reported a high intrasession reliability , 24, 27.Interestingly, considering all these limiting factors, the intra- and intersession reliability of the angle between PO and SP was high.Besides the commonly proposed criteria for a positive neurodynamic test, other variables may be considered to quantify neural mechanosensitivity. For the first time to our knowledge, the intra- and intersession reliability of the angle between PO and SP during the ULNT1 was specifically investigated and compared to the intra- and intersession reliability of PO and SP occurrence in the range. Measurement of the angle between PO and SP was more reliable than the measurement of PO and SP angles of occurrence in the range. Results were indicative of a high intrasession and a high intersession reliability. Taking this into account, the measurement of the angle between PO and SP may be a suitable (more reliable) alternative for the assessment of neural mechanosensitivity. Further research should focus on the reliability of this measurement in a clinical setting.


Among the existing f-divergences introduced in the process of finding the adequate distance between two probability distributions, let us point out the Csiszár f-divergence [Let us start with the notion of vergence , 2, somevergence , 4), thevergence , 6). Then-tuple n-tuple Jensen’s inequality, on the other hand, with its numerous refinements, variants and improvements is often called ‘a king inequality’, obviously not without a reason. Here we try to integrate one of such results concerning Jensen’s inequality in order to obtain new estimates for mentioned divergences . It is well known that the Jensen inequalityf defined on an interval n-tuple Here we cite a result of Pečarić , p. 717 f-divergences that originate from the Csiszár divergence functional.In recent investigations of relation  and its f-divergences are going to be observed here in the context of the Zipf–Mandelbrot law and then specified for the Zipf law.All of the results thus obtained concerning etc. Thus the term ‘Zipfian distribution’ is used to describe various types of distributions of the probability occurrences which approximately follow the mathematical form of the Zipf law. It was in the first place established with the frequency of the words in a text in view and as such it revealed a hyperbolic relation. As is e.g. explained in [f is inversely proportional to its rank r, or sequence number in the list and the product of these is a constant: George Kingsley Zipf 1902–1950) was a linguist after whom one of the most common laws in probability and statistics was named. Today this experimental law for the discrete probability distribution frequently is used in information science, bibliometrics, linguistics, social sciences, economy (where it is known as the Pareto law), as well as in physics, biology, computer science ained in , if word in 1966 , 15 acco in 1966 . It is a in 1966 , 18, in 02–1950 w in 1966 . The ZipN and for N and For finite According to the expressions above, the probability mass function referring to the Zipf law isf-divergences for which we give in Section The rest of the paper is organized as follows. In Section f-divergences were studied independently by several matematicians. Here we focus on the Csiszár f-divergences. Csiszár [f-divergence functional asThe previously mentioned  Csiszár , 2 introf-divergence functional .f. In the sequel we present some of the most frequent among them.The general aspect of the Csiszár divergence functional  can be ietc.Entropies quantify the diversity, uncertainty and randomness of a system. The concept of the Rényi entropy was introduced by  and has α of p is defined ase.g. the Hartley or max-entropy, min-entropy, and the collision entropy), the Rényi entropy tends to the Shannon entropy (see [The Rényi entropy of order opy (see ) for thef-divergence. The Rényi divergence of order α, Besides the absolute entropies, one can also observe the relative entropies, as did Rényi when he introduced a special form of nce (see ) for theAlthough it is common to take the logarithm function with the base 2, it will not be essential in the sequel. Moreover, we are going to analyze the results including the logarithm function for different (positive) bases, namely, for those greater than 1 as well as for those that are less than 1.Among various divergences and considering the properties of symmetry and triangular inequality which some of them possess, we can also define certain distances between two probability distributions.Thus the Hellinger distance between the probability distributions i.e. as The Hellinger distance is a metric and is often used in its squared form, α for the Rényi divergence, some have wider application than others. The value 1 is already determined by continuity in α since it cannot be calculated directly by  described in Section Letandben-tuples of nonnegative real numbers withandThenIt follows from Theorem If we observe (squared) Hellinger distanceIn other words, we obtained the corresponding bounds for the Letandben-tuples of nonnegative real numbers withandThenIt follows from Theorem If we observe finition  that \doBhattacharyya coefficientIn other words, we obtained the corresponding bounds for the Letbe ann-tuple of real numbers andann-tuple of nonnegative real numbers withandThenIt follows from Theorem If we observe chi-square divergenceIn other words, we obtained the corresponding bounds for the Letbe ann-tuple of real numbers andann-tuple of nonnegative real numbers withandThenIt follows from Theorem If we observe total variation distanceIn other words, we obtained the corresponding bounds for the Letbe ann-tuple of real numbers andann-tuple of nonnegative real numbers withandThenIt follows from Theorem If we observe triangular discriminationIn other words, we obtained the corresponding bounds for the In this section we are going to derive the results from the previous section for the Zipf–Mandelbrot law . Namely,,s,t) in  as its pq via \documentp and q defined via the Zipf–Mandelbrot law, then the following corollary plays a role.If we have both Letbe an interval and supposeare such thatIfis a convex function, thenwhereIffis a concave function, then the inequality signs are reversed.Ifis a convex function, thenwhereandIfis a concave function, then the inequality signs are reversed.f and Since the corollary is a special case of the previous one, its proof is provided by inserting equation , which dp and q are defined via the Zipf law 40) are pfined by . □f-divergences, starting with the Kullback–Leibler divergence , for the triangular discrimination , e.g. linguistics was involved in this case).In this paper we investigated


Robotic arm supports aim at improving the quality of life for adults with Duchenne muscular dystrophy (DMD) by augmenting their residual functional abilities. A critical component of robotic arm supports is the control interface, as is it responsible for the human-machine interaction. Our previous studies showed the feasibility of using surface electromyography (sEMG) as a control interface to operate robotic arm supports in adults with DMD (22-24 years-old). However, in the biomedical engineering community there is an often raised skepticism on whether adults with DMD at the last stage of their disease have sEMG signals that can be measured and used for control.In this study sEMG signals from Biceps and Triceps Brachii muscles were measured for the first time in a 37 year-old man with DMD (Brooke 6) that lost his arm function 15 years ago. The sEMG signals were measured during maximal and sub-maximal voluntary isometric contractions and evaluated in terms of signal-to-noise ratio and co-activation ratio. Beyond the profound deterioration of the muscles, we found that sEMG signals from both Biceps and Triceps muscles were measurable in this individual, although with a maximum signal amplitude 100 times lower compared to sEMG from healthy subjects. The participant was able to voluntarily modulate the required level of muscle activation during the sub-maximal voluntary isometric contractions. Despite the low sEMG amplitude and a considerable level of muscle co-activation, simulations of an elbow orthosis using the measured sEMG as driving signal indicated that the sEMG signals of the participant had the potential to provide control of elbow movements.To the best of our knowledge this is the first time that sEMG signals from a man with DMD at the last-stage of the disease were measured, analyzed and reported. These findings offer promising perspectives to the use of sEMG as an intuitive and natural control interface for robotic arm supports in adults with DMD until the last stage of the disease.The online version of this article (doi:10.1186/s12984-017-0292-4) contains supplementary material, which is available to authorized users. People with Duchenne muscular dystrophy (DMD) lose independent ambulation by the age of ten years, followed by the development of scoliosis and loss of upper extremity function during their teens, and develop severe cardiomyopathies and respiratory problems during their twenties . Life exSeveral arm supports that compensate the weight of the arms are commercially available and have shown an increase of independence and quality of life for teenagers with DMD . HoweverIn order to operate robotic arm supports, the user needs to communicate his motion intention to the device through a control interface. Currently, the only control interface available for adults with DMD are hand joysticks and switches, which are used to control wheelchairs and external robotic arms. We consider that the use of control interfaces that detect the motion intention from physiological signals that are implicitly related to the supported motion can result in a more natural and intuitive interaction with the robotic arm support. In this direction, we have developed and evaluated force and surface electromyography (sEMG) based control interfaces , 9.The ability for adults with DMD to use sEMG-based control, a well-established control interface in upper-extremity prosthetics , dependsIn a previous study , we showDMD patients at the last stage of their disease are very rare and getting them involved in any study is difficult and delicate, because they easily get overwhelmed by the exercises. As a consequence, conducting tests with even just a few of these subjects is very unlikely and general conclusions will have to be drawn from a number of independent studies. We were able to get the kind collaboration of a 37 year-old man with DMD for this study to evaluate his sEMG signals from upper-extremity biceps and triceps muscles. Albeit results from only one subject are insufficient to draw general conclusions, they are relevant to be communicated because of their exceptional nature and will encourage similar studies.While we hypothesized that the neural activation of the muscle is still measurable in men with DMD that have lost their arm function long time ago (DMD is a disease affecting the contraction of the muscle cells only), we expected their sEMG signals to have a much lower amplitude than in the case of healthy individuals: the infiltration of fatty and connective tissue in the muscle is known to increase the electrical impedance . The quaA 37 year-old man with DMD participated in this study. The participant was classified according to the Brooke upper extremity function scale  with a sThe sEMG signals were measured from the Biceps Brachii and Triceps Brachii muscles of the right arm, which originally was the dominant arm. Two 99.9% Ag parallel bars electrodes (contact: 10 mm x 1 mm each) spaced 10 mm apart  were placed in parallel with the muscle fibers following to the SENIAM recommendations  and manuThe sEMG signals were measured with a data acquisition card with a sampling frequency of 1 kHz and 16 bit resolution. The offset of the raw sEMG signals was removed on-line using a fourth-order Butterworth high-pass filter with a cutoff frequency of 20 Hz. Subsequently the signals were full-wave rectified and smoothed using a second-order low-pass Butterworth filter with a cutoff frequency of 1 Hz to obtain the signal envelope. The envelopes were used for the visual feedback during the maximal voluntary isometric contractions (MVIC) and sub-maximal voluntary isometric contractions (SVIC), for the analysis of the CAR, and for the simulation of the elbow orthosis.The participant was asked to perform a series of MVICs and SVICs with his biceps and triceps muscles. The MVIC were measured to investigate the maximal signal amplitude, and the SVIC were measured to investigate if the participant could voluntarily modulate the intensity of the muscle activation. Since the participant had not been able to voluntarily flex and extend his elbow joint for a long time, the examiner passively moved his elbow joint and applied pressure against the intended movement to familiarize the subject with the task. For the MVIC measurements the researcher asked the participant to maximally flex and extend his elbow during three seconds, three times for each muscle. For the SVIC measurements the subject was asked to reach three activation levels  during three seconds for each muscle. Note that the actual activation levels achieved by the participant were slightly different from these target levels see “” sectionThe quality of the sEMG signals was evaluated in terms of the SNR and the CAR. Additionally, the measured sEMG signals were used to drive a simulated elbow orthosis to evaluate the feasibility of using the sEMG signals for control purposes.SNRb) and of the triceps (SNRt) were calculated by taking the ratio between the power of the root-mean-squared amplitude of the raw sEMG signal  during the three MVIC and SVIC measurements, and the power of the RMS amplitude of the raw sEMG signal during a resting period, which represented the noise level : The SNR of the biceps  and triceps (CARt). The CAR was defined as the ratio between the RMS amplitude of the normalized sEMG signal envelope of the agonist muscle , and the RMS amplitude of the normalized sEMG signal envelope of the antagonist muscle  during the three MVIC and SVIC measurements  and triceps (RMSNt) were calculated by dividing the RMS value of the signal envelope  by the RMS value of the signal envelope of the MVIC  was subtracted from signal envelopes before calculating RMSNb and RMSNt. The normalized signal envelopes of the biceps  of a sEMG-controlled elbow orthosis. This method was chosen because the high intrinsic stiffness and contractures present in the elbow joint of the participant prevented the use of a real robotic elbow orthoses.Eb, Et) by a mapping gain  and subsequently subtracting the triceps signal from the biceps signal: The sEMG-based control method implemented in the simulation and described in this subsection was the same used in our previous study  were elbEb and Et. The offset value was calculated by taking the mean value of the signal envelope during three seconds while the participant was relaxed. For the simulation, the signals measured during the MVIC of the biceps and of the triceps : The estimated elbow torque was then used as input for an admittance model that rendered the dynamics of a mass-damper system and had as output the elbow angle  resulting from Eq. ; SNRb:2.17±0.5 (6.7±2 dB); Fig. The raw sEMG signals of the MVICs during three seconds presented maximum amplitudes of 0.01 and 0.015 mV for biceps and triceps muscles respectively . These Despite the deterioration of the muscles, we cannot underestimate the fact that sEMG signals from the biceps and triceps muscles were still measurable in a 37-year-old man with DMD that presented considerable muscle deterioration since 20 years ago and completely lost his arm function 15 years ago. Our results also indicate that the participant was able to adjust his voluntary isometric contractions as demanded by the exercises.The relevance of detecting measurable upper-extremity sEMG signals in adults with DMD at the late-stage of the disease extends beyond its clinical interest. sEMG signals can be used to detect the users’ motion intention and control rehabilitation or assistive devices, which have the potential to delay the disease progression and increase the quality of life for men with DMD , 27. On Currently, the use of robotic elbow orthoses in adults with DMD in the last stage of the disease is not an option due to the high intrinsic stiffness and joint contractures. However, the use of arm supports, would allow people with DMD to keep using their arms and therefore contribute to the delay of their functional deterioration. We expect that in the future, boys and men with DMD will use arm supports from an early age, which would preserve the range of motion of their joints and potentially benefit from the use of sEMG-controlled arm supports until the last stage of the disease.The results of the present case study indicate that sEMG signals from the biceps and triceps muscles were very deteriorated but still measurable in a 37 year-old man with DMD that lost his arm function several years ago. Also, the participant was able to adjust his muscle activation level as demanded by the SVIC tasks. To the best of our knowledge this is the first time that sEMG signals from a man with DMD at the last-stage of the disease were measured and reported. Despite the muscle deterioration, the measured signals could be successfully used as input for the control of a simulated elbow orthosis. These results offer promising perspectives to the use of sEMG as an intuitive and natural control interface for assistive devices in adults with DMD until the last stage of the disease, provided that the use of assistive devices since an early stage of the disease reduce joint stiffness and contractures.Results from only one subject are insufficient to draw general conclusions, but the difficulties to involve participants with DMD in the last stage of the disease make the inclusion of several patients in one single study highly complicated. Thus, sufficient evidence should come by integrating independent studies performed in different laboratories. We hope that the results presented in this Short Report will start breaking the current general opinion that sEMG signals are too weak in DMD patients at the last stage of the disease to be used for control, and will encourage similar studies in other parts of the world, finally leading to better assistive devices for adults with DMD.Additional file 1Raw sEMG signals during the biceps MVICs. MAT file containing two vectors of data (30001x1) of the raw sEMG signals of the biceps (EMGb) and the triceps (EMGt). Data was measured at 1 kHz. (MAT 421 kb)Additional file 2Raw sEMG signals during the triceps MVICs. MAT file containing two vectors of data (30001x1) of the raw sEMG signals of the biceps (EMGb) and the triceps (EMGt). Data was measured at 1 kHz. (MAT 424 kb)Additional file 3Raw sEMG signals during the biceps SVICs. MAT file containing two vectors of data (59806x1) of the raw sEMG signals of the biceps (EMGb) and the triceps (EMGt). Data was measured at 1 kHz. (MAT 854 kb)Additional file 4Raw sEMG signals during the triceps SVICs. MAT file containing two vectors of data (59706x1) of the raw sEMG signals of the biceps (EMGb) and the triceps (EMGt). Data was measured at 1 kHz. (MAT 853 kb)Additional file 5Additional results of the simulation of the sEMG-controlled elbow orthosis. PDF file showing two figures with additional results of the simulation of the sEMG-controlled elbow orthosis. (PDF 899 kb)


Recent media reports have highlighted the risks to patients that may occur when practitioners in the chiropractic, osteopathy and physiotherapy professions provide services in an unethical or unsafe manner. Yet research on complaints about chiropractors, osteopaths, and physiotherapists is limited. Our aim was to understand differences in the frequency and nature of formal complaints about practitioners in these professions in order to inform improvements in professional regulation and education.This retrospective cohort study analysed all formal complaints about all registered chiropractors, osteopaths, and physiotherapists in Australia lodged with health regulators between 2011 and 2016. Based on initial assessments by regulators, complaints were classified into 11 complaint issues across three domains: performance, professional conduct, and health. Differences in complaint rate were assessed using incidence rate ratios. A multivariate negative binomial regression model was used to identify predictors of complaints among practitioners in these professions.p < 0.001). Among chiropractors, 1% of practitioners received more than one complaint – they accounted for 36% of the complaints within their profession.Patients and their relatives were the most common source of complaints about chiropractors, osteopaths and physiotherapists. Concerns about professional conduct accounted for more than half of the complaints about practitioners in these three professions. Regulatory outcome of complaints differed by profession. Male practitioners, those who were older than 65 years, and those who practised in metropolitan areas were at higher risk of complaint. The overall rate of complaints was higher for chiropractors than osteopaths and physiotherapists (29 vs. 10 vs. 5 complaints per 1000 practice years respectively, Our study demonstrates differences in the frequency of complaints by source, issue and outcome across the chiropractic, osteopathic and physiotherapy professions. Independent of profession, male sex and older age were significant risk factors for complaint in these professions. Chiropractors were at higher risk of being the subject of a complaint to their practitioner board compared with osteopaths and physiotherapists. These findings may assist regulatory boards, professional associations and universities in developing programs that avert patient dissatisfaction and harm and reduce the burden of complaints on practitioners. Amongst the 15 regulated health professions in Australia, three professions deal with musculoskeletal complaints as a major component of their work. Recent media reports have highlighted the risks to patients that may occur when practitioners in the chiropractic, osteopathy and physiotherapy professions provide services in an unethical or unsafe manner . ComplaiPrevious studies have identified differences in the rate of patient complaints between chiropractors, osteopaths, and physiotherapists  and betwIn the current study, we used comprehensive national data on all registered chiropractors, osteopaths, and physiotherapists in Australia, and formal notifications of concern (“complaints”) to regulators about these practitioners, to better understand complaint risk across these three professions. We aimed to compare the risk of complaint among chiropractors, osteopaths, and physiotherapists and to locate any increased risks in specific aspects of clinical practice.In Australia, chiropractors, osteopaths and physiotherapists are registered by three regulatory boards - the Chiropractic Board, the Osteopathy Board, and the Physiotherapy Board – under the umbrella of a national health practitioner regulation scheme. Together these professions make-up around 6 % of the registered health workforce in Australia. They are the only practitioners  permitted to perform manipulation of the cervical spine under the National Law . They arThere are some important contextual differences between the professions. Physiotherapy is the largest and the longest-established of the three professions in Australia . Formal In contrast, chiropractic and osteopathy are smaller professions in Australia and their assimilation into regulatory and university frameworks occurred later , 12. StaWe obtained and linked two datasets: 1) a register dataset that covered all chiropractors, osteopaths, and physiotherapists registered to practice in Australia between 1 January 2011 and 31 December 2016; and 2) a complaints dataset that covered all health, performance, and conduct concerns about this group of practitioners lodged with health regulators during the same period.The register dataset was provided by the Australian Health Practitioner Regulation Agency (AHPRA), a national agency working in partnership with national health practitioner boards who have responsibility for overseeing practitioners in 15 health professions. APHRA maintains a register of practitioners. We obtained a de-identified extract containing information on all chiropractors, osteopaths, and physiotherapists registered for any period of time during the study period in all of Australia’s states and territories. The extract included information on the practitioner’s age , sex, specialty, and state or territory of practice; the geographic remoteness of their practice location (“practice location”); and dates during which they were registered. Practitioners who held registration in more than one profession (163 practitioners) were randomly allocated into one of those professions. We excluded practitioners registered to addresses outside Australia and those who held non-practising registration. In Australia, practitioners are considered to be practicing when using the knowledge and skills of their profession in their employment, so practice includes teaching and academic roles.Although practitioners from all three professions are registered with the relevant national board, complaints about practitioners in New South Wales (NSW) are managed by the state based Health Professionals Council Authority (HPCA) in conjunction with the Health Care Complaints Commission and, since July 2014, complaints about practitioners in Queensland are made through the Office of the Health Ombudsman (OHO) . The comThe primary matter of concern raised in each complaint was coded into 11 complaint issues and three domains . Performance-based complaints relate to knowledge, skill, judgement or care that is of a lower standard than can be reasonably be expected. Conduct-based complaints relate to unethical or illegal conduct. Health complaints relate to physical or mental conditions that may impair a practitioner’s ability to practice safely. The coding of complaint issues was based on initial assessments by AHPRA and HPCA staff of the primary issue raised by the complaint: two researchers working independently grouped 149 codes used by these agencies into the 11 complaint issues most commonly raised in relation to these three professions. Any discrepancies were resolved by consensus. These codes were mutually exclusive, with each complaint assigned to only one complaint issue and one domain  the amount of time in the study period each practitioner was registered (denoted as fractions of years); and (2) the average number of clinical hours worked per week . The amount of time each practitioner was registered was calculated directly from the AHPRA register data. Our estimate of clinical hours per week was based on publicly reported information from the 2015 Health Workforce Survey,  using thWe used counts and percentages to describe the characteristics of practitioners and complaints about them, stratified by profession . We also used counts and percentages to describe the source, complaint issue, and outcome of complaints. Overall significant difference among profession for each characteristic was analysed using the chi-square test.As the absolute numbers of complaints regarding osteopaths were low, a robust between-profession comparison involving complaints about osteopaths was not possible. We therefore conducted analyses comparing the incidence rate of complaints about chiropractors and physiotherapists within each of the three domains  and 11 complaint issues . We used incidence rate ratios (IRRs) to indicate the ratio of the complaint rate amongst chiropractors to the complaint rate amongst physiotherapists, after adjusting for practice years.Finally, we performed multivariate negative binomial regression analysis to assess the associations between profession, age, sex, practice location and complaint risk across the three professions. The regulators in our study routinely collect these variables and they have previously been shown  to be associated with complaint risk , 20. ThiWhile advertising complaints are primarily dealt with as a statutory offence under the National Law managed by AHPRA, some are referred on to Boards to be dealt with as conduct concerns . Given rp < 0.001). Chiropractors were more likely to be aged over 36 years , male , and to practice in non-urban areas .During the study period there were 5450 chiropractors, 2241 osteopaths, and 31,534 physiotherapists registered to practice in Australia  A total of 1139 complaints about chiropractors, osteopaths and physiotherapists were lodged during the study period.p < 0.001). Overall, nearly half of the complaints (47.7%) involved chiropractors, even though chiropractors make up less than one-sixth (13.9%) of the workforce across these three professions.As a group, chiropractors had a higher overall rate of complaints (29 complaints per 1000 practice years) than osteopaths and physiotherapists  were subject to more than one complaint: these practitioners were responsible for over a third (35.5%) of the complaints about chiropractors. Among osteopaths, 0.4% (n = 9) accounted for 26.3% of complaints, and among physiotherapists 0.1% (n = 40) accounted for 18.7% of complaints.A small group of practitioners were the subject of multiple complaints. Just over 1 % of chiropractors  raised concerns about the practitioner’s professional conduct; approximately one third (29.1% and 32.9%) related to performance issues; and few (2.8% among chiropractors and none among osteopaths) raised concerns about a possible health impairment (Table The outcome of complaints varied by profession Table . Among cp < 0.001).The overall complaint rate for practitioners in the chiropractic, osteopathy and physiotherapy professions was 8 complaints per 1000 practice years. The complaint rate for chiropractors was three times higher than for osteopaths and six times higher than for physiotherapists , around eight times higher for professional conduct concerns , and nearly three times higher for health concerns  , sexual boundaries , fees/honesty , and interpersonal behaviour . Due to the low absolute number of complaints for osteopaths we did not conduct a similar comparison for osteopaths.Table Our aim was to understand differences in the rates and patterns of formal complaints about Australian health practitioners in three health professions: chiropractic, osteopathy and physiotherapy.During the study period 39,225 practitioners were registered to practice in these professions in Australia. The vast majority of practitioners  were not subject to any complaints to regulators during the study period. Among the 1139 formal complaints about chiropractors, osteopaths and physiotherapists lodged with regulators in Australia over the six-year period, we found that chiropractors had a higher rate of complaints than osteopaths and physiotherapists.Within the chiropractic profession, over one third of complaints (36%) were about a small number of practitioners (1.3%). This finding that complaints clustered amongst a relatively small number of practitioners is consistent with previous research about medical practitioners . A focusThe most common source of complaints for all three professions was patients or their relatives. Nearly 8% of physiotherapy complaints came from their employers, which may reflect the fact that physiotherapists are more likely to work as employees within public sector organisations [Within our 11 complaint issues, complaints related to treatment made up around one fifth of all complaints within each profession suggesting this is an important focus of monitoring and education for all three professions. A finer grained classification of concerns about treatment may provide important direction for future research, and subsequent work in education and remediation - for example, a UK study of osteopathic complaints found clinical care concerns were most commonly around inappropriate treatment, or treatment not justified, forceful treatment, treatment that caused new or increased pain or injury, and treatment administered incompetently .Around two-thirds of the complaints about chiropractors and osteopaths raised concerns about professional conduct. One-fifth of complaints about chiropractors related to advertising or fees/honesty. This may reflect increased involvement in private practice – in other words, a heightened level of exposure to such complaints that we could not control for – or inappropriate practice building strategies and small business financial pressures, and this provides an important direction for work in the profession. More than one quarter of complaints about osteopaths related to sexual boundaries or interpersonal behaviour. While absolute numbers are low, measures to monitor and address these areas are likely to be of importance to the osteopathic profession.We identified differences in regulatory outcomes between the professions: in particular, complaints about osteopaths were more likely to be referred to another agency while complaints about chiropractors took longer to resolve, and were more likely to result in serious outcomes, such as imposition of conditions or suspension of registration, than those involving physiotherapists. Further work is required to understand whether this reflects unintended variation in decision-making between the Boards, or differences in the severity of complaints received about these professions. While over half the complaints across all three professions resulted in no further action, it is important to note that no further action does not necessarily mean a complaint had no substance: it is a common outcome in situations where a practitioner has already taken appropriate steps to address the concerns raised by the complainant.The higher rate of complaints about chiropractors (compared with physiotherapists), relating to advertising/titles, fees/honesty, sexual boundaries, and interpersonal behaviour (such as bullying and disrespect) could provide useful direction for future research, and highlights the importance of ethics and professionalism in clinical practice.The finding that older and male practitioners had a higher rate of complaints than female practitioners is consistent with Australian and international studies in medicine , 20, 24.In relation to the difference between male and female practitioners, our analyses controlled for age, duration of registration to practice, and hours of practice, suggesting that the increased complaints rate among male practitioners is not simply due to differences in the practitioner population or time spent in clinical practice. Previous research with medical doctors has identified differences in communication skills between male and female practitioners, which may account for some of these differences .A key strength of our study is its comprehensiveness. The analysis covered every registered chiropractor, osteopath and physiotherapist in all states and territories in Australia over a six-year study period. Normally, such breadth comes with a substantial trade-off in depth. However, the detailed data on practitioner demographic characteristics and the complaints lodged allowed us to disaggregate complaint rates in a variety of ways, while accounting for clinical hours worked and duration of registration.Our study has three main limitations. First, complaints are an imperfect indicator of quality of care; they offer only one window into concerns about clinical practice. Previous research suggests that most instances of poor performance, impairment, or unethical conduct do not result in a formal complaint . Second,Health practitioner regulators are charged with protecting the public from harm . Our aimWe found differences in the frequency of complaints by issue within the professions. Male practitioners, and those aged 65 years or older had a higher complaint rate independent of their profession. Chiropractors had a higher complaint rate for being the subject of a complaint or concern to their practitioner board compared with osteopaths and physiotherapists. Hotspots of complaint risk for chiropractors  include advertising/titles, fees/honesty, sexual boundaries and interpersonal behaviour.Our study highlights a number of areas for future research both within and across the professions. In particular, the impact of profession-specific techniques, patient volume, group practice, interdisciplinary integration, and evidence-based approaches to practice are important foci for future research on complaint risk in these professions.Programs designed to address hotspots of complaint risk for these professions may help to avert patient dissatisfaction and harm and reduce the burden of complaints on practitioners. Regulatory boards, professional associations and educational bodies may find these data helpful in designing further research and developing interventions that support practitioners in the chiropractic, osteopathy and physiotherapy professions to improve the experience of their patients.


N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood . The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an  Recent meta-analyses on inflammation in suicidal patients conclude that there are aberrant cytokine levels in blood, cerebrospinal fluid (CSF), and post-mortem brain samples from suicidal patients.4 Increased blood levels of tumor necrosis factor-α, interleukin-1β (IL-1β) and IL-6 are associated with suicidal ideation and behavior, and therefore these cytokines have been proposed to constitute biomarkers to help distinguish suicidal from nonsuicidal patients.6 We have found that the CSF levels of IL-6 were increased threefold in patients who recently attempted suicide compared with healthy controls.7Suicide is defined as the intentional termination of one's own life, and constitutes the 10th leading cause of death globally.8 (10 QUIN is an N-methyl-d-aspartic acid receptor (NMDA-R) agonist that in the central nervous system is formed to a large extent within microglial cells. QUIN is a potent excitotoxin with proinflammatory and immunoregulatory properties.9 In addition to being a direct NMDA-R agonist, QUIN increases neuronal glutamate release and decreases glutamate uptake and recycling by astrocytes.9 Consequently, QUIN has dual effects on NMDA-R, both acting as an agonist and increasing extracellular glutamate levels. Ketamine, an NMDA-R antagonist, has proven effective in counteracting suicidal ideation in several clinical studies, highlighting the role of glutamate neurotransmission in suicidal patients.12 In mice, inflammation-induced depressive-like behavior can be reversed by ketamine, providing further support for an association between inflammation, NMDA-R activation and depression.13 It has been proposed that production of the NMDA-R agonist QUIN is the mechanistic link between inflammation and symptoms of depression and suicidality.15Some of the effects of inflammation on mood and behavior may be mediated by kynurenine pathway metabolites, which modulate neuroinflammation and glutamate neurotransmission. More than 90% of dietary tryptophan is degraded along the enzymatic kynurenine pathway, and in the process several neuroactive compounds are formed, including quinolinic acid (QUIN) and picolinic acid (PIC)8 . Proinfl15 Other groups have also detected increased QUIN staining in post-mortem brain sections from patients with severe depression who committed suicide.16 QUIN is produced by the spontaneous conversion of the precursor metabolite 2-amino-3-carboxymuconate-6-semialdehyde , on suicidal behavior and levels of QUIN in CSF.We have discovered a threefold increase in the levels of QUIN in the CSF of suicidal patients compared with healthy controls.de ACMS; . HoweverOur study was carried out in accordance with ‘The code of ethics of the world medical association (Declaration of Helsinki)' for experiments including humans. The Regional Ethical Review Boards in Lund, Linköping, Malmö and Stockholm, approved the study. After complete description of the study, written informed consent was obtained from all subjects. 15Sixty-four patients (30 men and 34 women) were enrolled following admission to Lund University Hospital after a suicide attempt (see below for definition) between 1988 and 2001. Psychiatric diagnoses and demographics of the subjects are displayed in 23 with participants scoring 8 or above being excluded. A somatic examination was performed as described below for all subjects.Seventy-three patients (31 men and 42 women) admitted to Lund University Hospital, Sweden, after a suicide attempt between 2006 and 2010 were enrolled. Only patients with an explicit intent were enrolled . The patients had various psychiatric diagnoses and the majority were treated with pharmacological drugs. et al.24).Whole blood for genotyping was available from 227 individuals, including 77 suicide attempters from both the CSF and the plasma cohort. In addition, a cohort of 150 population-based healthy controls was genotyped. These were randomly selected by Statistics Sweden (SCB) and contacted by mail with a request for them to contact study nurse if interested in participating in the study. Following a preliminary telephone screening, eligible persons were interviewed by experienced psychiatrists using Mini International Neuropsychiatric Interview to exclude psychiatric disorders. AUDIT and the Drug Use Disorders Identification Test (DUDIT) were used to exclude substance abuse. Apart from psychiatric disorders, other excluded diagnoses were neurological conditions other than mild migraines, untreated endocrinological disorders, autoimmune disorders, pregnancy and a family history of schizophrenia or bipolar disorder in first-degree relatives. All controls were born in Sweden, as were their parents . Twenty-nine patients (9 men and 20 women) with a mean age of 40±9 years (mean±s.d.) were included between 1987 and 1992. A total of 143 CSF samples were collected from these individuals at time points when they were also assessed using the Montgomery Asberg Depression Rating Scale (MADRS) and the Suicide Assessment Scale (SUAS) as described.26 We evaluated the severity of depressive symptoms using the Montgomery-Åsberg Depression Rating Scale (MADRS), which is a 10-item scale with a maximum score of 60 derived from CPRS.27 The Suicide Assessment Scale (SUAS) is an interview-based scale, consisting of 20 items assessing signs and symptoms related to current degree of suicidality and has a maximum score of 80.28 SUAS has been validated in predicting future suicides.30Briefly, after the suicide attempt, a psychiatrist diagnosed all patients according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IIIR Axis I and II Disorders. The diagnoses were set by the psychiatrist after an ~2-h-long structured interview using the Comprehensive Psychiatric Rating Scale (CPRS) and the Structured Clinical Interview for DSM Disorders (SCID I and II). The CPRS is a widely used rating instrument in psychiatric research and consists of 65 scaled items, covering a wide range of psychiatric symptoms.31 Moreover, to be enrolled, the intent to commit suicide had to be explicit upon the clinical interview. Patients who did not state a clear intent were not enrolled. Suicide attempts were classified into violent and non-violent acts as previously defined.32 Drug-overdoses, single wrist-cuts or a combination are considered non-violent suicide attempts, whereas all other methods  were classified as violent.A suicide attempt was defined as ‘situations in which a person has performed an actually or seemingly life-threatening behavior with the intent of jeopardizing his/her life'.All patients and controls in the plasma and CSF cohorts underwent a general physical examination. In order to identify subjects with potential infections at the time of the lumbar punctures and blood samples, we analyzed blood samples for white blood cell count, erythrocyte sedimentation rate or C-reactive protein, and the subjects were checked for fever. No evidence of ongoing clinical infection was found, as defined by the normal reference intervals of these parameters. A complete medical history was taken. Somatic diagnoses of the subjects are shown in CSF was obtained from the L4–L5 interspace, using a standardized protocol. The CSF samples were drawn between 0800 and 1100 hours after a night of fasting and bed rest. The CSF samples were kept on ice during the sampling and thereafter immediately aliquoted and frozen at −80 °C. Blood samples were collected between 0730 and 0800 hours after a night of fasting and bed rest. The suicidal patients were psychiatric inpatients, whereas the control-groups had spent the night at home. The blood was placed on ice and centrifuged  within 1 h. Plasma was collected and stored at −80°C within 1 h after sampling. All blood and CSF samples were kept at −80 °C until analyses. The analysis of PIC, QUIN, kynurenine and tryptophan levels in blood and CSF as well as genotyping were performed by staff blinded to the experimental groups, with samples coded.w+v) in equal volume and incubated in ice for 5 min, vortexed and then centrifuged (4 °C) for 10 min at 12 000 r.p.m. Supernatant was carefully extracted and filtered with a 0.22 μm syringe filter . QUIN and PIC levels in CSF and plasma were examined using gas chromatography–mass spectrometry with the spectrometer operating in electron-capture negative-ionization mode. The method used is described in Smythe et al.33 The internal standards were purchased from Le Research . Trifluoroacetic anhydride and 1,1,1,3,3,3-hexafluoro-2-propanol of GC derivatization grade, QUIN, PIC and other organic solvents of analytical-grade were all obtained from Sigma-Aldrich . One microliter of sample was injected into an Agilent 6890 gas chromatograph, interfaced to an Agilent 5973 mass selective detector via an auto-sampler Agilent Technologies 7683, and controlled using Agilent ChemStation software . The inter- and intra-assay coefficient of variation was <5%.To extract KP metabolites, samples were treated with trichloroacetic acid at a final concentration of 5%  maintained at 38 °C for 12 min run time at a flowrate of 0.75 ml min−1 using 0.2 mm sodium acetate (pH 4.65) as mobile phase. Kynurenine was detected using ultraviolet wavelength at 365 nm, whereas tryptophan was detected using fluorescence intensity set at excitation/emission wavelength of 280/438 nm. Mixed standards of both metabolites were used for a six-point calibration curve in order to interpolate the quantity of the sample readout using Agilent OpenLAB CDS Chemstation (Edition C.01.04) to analyze the chromatogram. The inter- and intra-assay coefficients of variation were within the acceptable range of 3–7%.Kynurenine and tryptophan were concurrently measured using Agilent 1290 ultrahigh-performance liquid chromatography as previously described.−1. All samples were within the detectable range.Neopterin concentrations were determined by a commercially available ELISA 99R.096  following the manufacturers' instructions. Sensitivity of the test was 2 nmol lACMSD (±20 kB) were chosen using Tagger .35 SNP genotyping  were carried out using 5' nuclease assay chemistry with custom KASP technology probes36 at the Genomics Core Facility at the University of Gothenburg, Sweden. One SNP (rs6730306) failed at assay design. No systematic difference in individual missingness percentage was seen across the two cohorts of patients and controls. All markers had <10% missing data and none displayed a significant deviation from the Hardy–Weinberg equilibrium.Tag SNPs for https://www.r-project.org/). The power calculation was based on variance and mean levels of inflammatory factors in suicide attempters versus controls detected in our previous studies. Mean PIC case concentration was estimated at 175 nm and control concentration at 250 nm. Pooled sample s.d. across the two samples was estimated to be 150 nm. Power was computed for a two-tailed t-test and 84% power is achieved with n=35 per group. In plasma, PIC, QUIN and the kynurenine/tryptophan ratios displayed a non-normal distribution and non-parametrical tests were used for groupwise comparisons and correlations. For linear regression, the measures were transformed into normal distribution by logarithm. CSF analytes displayed a normal distribution. Groupwise comparisons were performed using independent samples t-test or U-tests. Correlations were performed using Pearson's R or Spearman's Rho. A linear mixed-effects model with random slopes was used to determine whether CSF levels changed over the 2 years following a suicide attempt. The model was originally adjusted for age and gender; although as no evidence was found that these impacted CSF levels, they were subsequently omitted in the final model. The delta method was used to test whether controls differed from the index CSF levels of suicide attempters, where the mean index CSF was estimated by the linear mixed-effects model. For the genetic analyses, we used the subsample of patients and controls with available CSF QUIN, PIC and kynurenine data. We applied simple linear regression models to study the effect of ACMSD tag SNPs variants on CSF levels of QUIN, the QUIN/PIC ratio (log transformed), and kynurenine. Common genetic variants that were significantly associated with CSF levels of QUIN, after adjustment for multiple comparisons (Bonferroni correction), were analyzed in cases versus controls using logistic regression with adjustment for age and sex. All genetic analyses were performed using an additive model. All reported P-values are two-sided and analyses were performed using either IBM SPSS Statistics 20.0 or PLINK (http://pngu.mgh.harvard.edu/purcell/plink/).37All statistical analysis, except the longitudinal CSF analysis, was performed using the Statistical Package for the Social Sciences ). The longitudinal analysis was performed using R v 3.2.2 (P<0.05), but not with gender, body mass index or age of samples ). The PIC data in CSF was therefore corrected for subject age in all subsequent groupwise comparisons. The kynurenine/tryptophan ratio in CSF was associated with age and gender of subjects and was therefore corrected for these covariates in groupwise comparisons. PIC in plasma was not associated with any of the mentioned co-variates, whereas the plasma kynurenine/tryptophan ratio and plasma QUIN were associated with the age of subjects and therefore corrected for this in all subsequent groupwise comparisons.The levels of PIC in CSF were associated with the age of the subject  compared with healthy controls .No significant differences in CSF PIC levels were found between the five largest diagnostic groups of the patients , NS). The mean CSF PIC concentrations in the main diagnostic groups and controls are shown in n=16) and non-violent attempts (n=48), or between patients who had previously performed attempts (n=22) versus first-time suicide attempters (n=42) .There was no difference in CSF PIC levels between violent . A total of nine patients took other medications , the mean CSF PIC values of the patients were significantly lower than the value obtained from healthy controls  . There was no evidence of a gender difference in either the control group or the patient group.As a secondary analysis of the same population, a linear mixed-effects model with random slopes was fit to determine whether PIC CSF scores changed over time for the patient group, taking all samples into account, at each individual time point. PIC levels did not change significantly over time (estimate=0.56 n P=0.11) . The deln=73) compared with controls  and plasma QUIN  in the patients (n=54) but not in the healthy controls (n=29).Similar to the results in the CSF cohort, the levels of PIC were decreased in plasma of suicide attempters (n=22) that received propiomazine, an antihistamine used for improved sleep, had higher levels of PIC in plasma. Because this effect cannot be a confounder of the result of significantly reduced PIC in plasma of patients, we did not correct for this effect. A total of 14 patients were untreated .ACMSD variants on CSF QUIN levels in all genotyped patients and controls with available CSF data . Among the seven tag SNPs only rs2121337  remained significant post Bonferroni correction  . Further, adding age and sex as covariates had little impact on the association . Using the same sample, the minor C allele of rs2121337 was also associated with an increased CSF QUIN/PIC ratio .First we studied the effect of ACMSD, rs2121337, was coupled to increased QUIN in CSF and was more prevalent in suicide attempters than healthy controls. Hence, we obtained support for our primary hypothesis, namely that a reduced ACMSD activity underlies excess QUIN production observed in patients exhibiting suicidal behavior. The reduced activity could be due to either a decreased enzymatic function or to a reduced tissue expression of the enzyme. As QUIN is an NMDA-R agonist and has additional enhancing effects on glutamate neurotransmission and neuroinflammation, reduced ACMSD function could contribute to a vicious circle with increased neuroinflammation being established in vulnerable patients. Altogether, our data indicate that ACMSD is a potential regulator of vulnerability/resilience to suicidal behavior upon inflammatory challenges.To our knowledge, our study provides the first evidence of reduced levels of PIC in CSF and blood in conjunction to a suicide attempt in two independent cohorts, as well as over a longitudinal follow-up period in patients initially enrolled in the CSF cohort. Moreover, we observed the same biological alterations in suicide attempters that were medication free (the CSF cohort) and in attempters that received different psychotropic medications (the plasma cohort). Our pilot genotyping study indicated that a SNP of 38 The expression and activity may also be induced in other tissues based on dietary or metabolic conditions,43 although the full tissue range of expression still remains to be characterized. The biological factors regulating the expression and activity of ACMSD in neurons and astrocytes are not yet well established. Genetic variants of ACMSD have previously been associated with differential expression of the enzyme in brain tissue in patients with Parkinson's disease.44 The purpose of including the tag SNP data in our current study was to perform a small, hypothesis driven verification of a possible involvement of a few SNPs in the ACMSD region. Our analyses differ from a genome-wide association study approach as we only included ACMSD tag SNPs in our analyses and selected candidate risk variants based on association with QUIN levels in CSF. Our sample size using this approach is inevitably limited and our data have to be interpreted with caution until replicated in larger studies. Nonetheless, these genetic analyses complement our patient versus controls analyses of CSF and plasma concentrations, and provide further support for a direct role of ACMSD function in suicidal behavior.ACMSD is expressed in liver and kidney as well as in neurons and astrocytes of the central nervous system.25 In addition, as the increased production of QUIN is by itself proinflammatory it can lead to increased microglial activation and secretion of proinflammatory cytokines.9 Thus, a reduced amount or activity of ACMSD within the central nervous system can predispose to the development of a chronic inflammatory environment, potentially with the capability of becoming self-sustained even after cessation of proinflammatory stimuli originated in the periphery. Conversely, in healthy subjects, constitutionally high ACMSD activity could be protective, contributing to shunting of kynurenine metabolism toward the production of the neuroprotective PIC and away from the neurotoxic QUIN, preventing a vicious circle generating inflammation and inflammatory metabolites.We studied the levels of PIC in CSF in a follow-up study over 2 years after an initial suicide attempt. Because the patients were not actively suicidal at the follow-up time points, we were able to study the CSF levels of PIC without any potential influence of a physical suicide attempt . We observed that the levels of PIC in CSF were reduced compared with controls at all time points, which indicates that decreased ACMSD activity may be a trait-marker of patients prone to suicidal behavior, rather than a state-marker. One could propose that an innate reduced biological activity of the ACMSD enzyme would make patients more susceptible to inflammatory conditions, as they would produce more QUIN upon inflammatory stimuli. In fact, we have shown that in patients with elevated QUIN the depressive and suicidal symptoms fluctuated over time with varying degree of inflammation in the CSF and blood.25 Therefore, our results primarily suggest that ACMSD could be important in the pathogenesis of suicidality based on its capability to reduce QUIN levels. Indeed, a study by Walker et al.13 showed that depressive-like behaviors induced by endotoxin injections (inducing inflammation) in rodents were reversed by the effects of ketamine on the NMDA receptor. Ketamine is an NMDA-R antagonist, with the potential of counteracting effects of the NMDA-R agonist QUIN. However, one should also consider that PIC itself could influence the pathogenesis of psychiatric disease. The neuroprotective mechanisms of action of PIC are not fully understood, but it is well known that PIC acts as a metal chelator.17 Bound to chromium, PIC has been shown to reduce symptoms in patients with atypical depression.45 PIC also exerts growth-factor-like properties, by inducing the production of macrophage inflammatory protein-1α and -1β as well as vascular endothelial growth factor, a potent neuroprotective agent,47 and can moreover induce the differentiation of stem cells.48 Rodent studies have indicated that PIC may protect against depressive- and anxiety-like behaviors.51We have previously shown that the degree of symptoms in patients exhibiting suicidal behavior is related to inflammation and QUIN levels in CSF.et al.52 have previously demonstrated that the kynurenine pathway is induced in the peripheral blood of suicidal patients, as evidenced by an increased kynurenine/tryptophan ratio, although they did not attempt to measure QUIN or PIC. In the current study, we observed increased kynurenine/tryptophan ratio in the CSF of the patients, but not in their peripheral blood; however, we found that the peripheral ratio was significantly associated with plasma neopterin levels in suicide attempters. Neopterin is synthesized and released primarily from human monocyte-derived macrophages and dendritic cells upon activation with IFN-γ22 therefore, elevated neopterin levels are usually accompanied by enhanced tryptophan breakdown because indoleamine 2,3 dioxygenase is upregulated by the same proinflammatory stimuli.53 This finding demonstrates a proinflammatory status in the blood of suicide attempters, so although our primary indicative is central nervous system inflammation, our study also points towards involvement of the peripheral immune system in the suicide attempters. In line with these findings it is important to note that the decreased activity or expression of ACMSD is readily detectable in blood by using PIC and QUIN levels as biomarkers. Therefore, we have identified both a plausible biological mechanism for the increased QUIN levels detected in suicide attempters (reduced activity or expression of ACMSD) and a peripheral biomarker that might indicate suicide risk (the plasma PIC/QUIN ratio).Although the findings of reduced PIC and increased QUIN are most pronounced in the CSF of the suicide attempters, the PIC levels are also significantly reduced in peripheral blood, opening up the possibility of assessing PIC, or the ratio of PIC/QUIN in the blood as a potential risk marker of suicidal behavior. Sublette et al.,54 who found post-mortem signs of brain inflammation in patients who died from suicide, irrespective of their primary diagnosis.Even though this study uses multiple cohorts and analyses both longitudinal and cross-sectional data as well as genotyping, we do not test any direct causality of increasing or decreasing the activity of ACMSD. Such mechanistic studies of causality should be undertaken in animal models of depressive-like behavior, and would further strengthen the implication of ACMSD as a potential target for pharmacological modulation in patients with suicidal behavior. Moreover, we do not know whether exogenous inflammation was the initial trigger of the observed changes in the patients, or whether a decreased enzymatic activity of ACMSD is sufficient to trigger a proinflammatory environment by itself. As we did not include any psychiatric control group, it will be important to define whether the changes in ACMSD biological activity are specific for suicidal behavior, or whether they also extend to other underlying psychiatric conditions. Notably, we did not detect any differences in the levels of PIC in CSF or blood between any of the diagnostic groups assessed here, which may suggest that changes in the kynurenine pathway are specifically associated with suicidal behavior, not with the primary diagnosis. A similar observation was made by Steiner In conclusion, we have found that the neuroinflammation and excess QUIN previously observed in patients exhibiting suicidal behavior may be due to deficient activity of ACMSD, an enzyme of the kynurenine pathway that regulates the formation of the NMDA-R agonist and neurotoxin QUIN. Modulating ACMSD might represent a future strategy for the development of novel anti-suicidal pharmacological tools. Blood measurements of PIC and QUIN might prove useful as biomarkers in order to identify patients vulnerable to develop suicidal behavior.