E. coli. The inner membrane transporter AcrB is a homotrimer, energized by the proton movement down the transmembrane electrochemical gradient. The asymmetric crystal structures of AcrB with three monomers in distinct conformational states  support a functional rotating mechanism, in which each monomer of AcrB cycles among the three states in a concerted way. However, the relationship between the conformational changes during functional rotation and drug translocation has not been totally understood. Here, we explored the conformational changes of the AcrB homotrimer during the ABE to BEA transition in different substrate-binding states using targeted MD simulations. It was found that the dissociation of substrate from the distal binding pocket of B monomer is closely related to the concerted conformational changes in the translocation pathway, especially the side chain reorientation of Phe628 and Tyr327. A second substrate binding at the proximal binding pocket of A monomer evidently accelerates the conformational transitions as well as substrate dissociation in B monomer. The acceleration effect of the multi-substrate binding mode provides a molecular explanation for the positive cooperativity observed in the kinetic studies of substrate efflux and deepens our understanding of the functional rotating mechanism of AcrB.The tripartite efflux pump assembly AcrAB-TolC is the major multidrug resistance transporter in  Escherichia coli has been extensively studied as a prototype of the family, which exports a number of dyes, detergents, chloramphenicol, tetracyclines, macrolides, β-lactams, fluoroquinolones, and organic solvents. It functions in the form of AcrAB-TolC tripartite complex  superfamily proteins play a major role in the efflux of a wide range of antibiotics and toxic compounds out of cell. RND superfamily, together with other classes of multidrug efflux pumps, constitute one of the major mechanisms of multidrug resistance (MDR) in bacteria, which represents a serious impediment to improved healthcare Higgins, . RND traCrystallographic studies have revealed the structure of AcrB as a homotrimer  was used as the starting structure of all simulations. In the crystal structure, residues 1034–1049 are missing in chain A and C, and residues 1046–1049 are missing in chain B. To keep the 3-fold symmetry of the protein, we truncated the residues 1034–1045 in chain B. Since no substrate was cocrystallized in this structure, one doxorubicin was docked into the DBP of B monomer according to the AcrB-doxorubicin complex structure (PDBID: 2DR6). In the simulations with two substrates, the second doxorubicin was docked into the PBP of A monomer by using Autodock   bilayer consisting of 512 lipid molecules following the “shrinking” method  method , followed by a 4 ns run without any restraint. AcrB was stable in the 4 ns NPT run with its Cα root-mean-square deviation (RMSD) relative to the initial crystal structure fluctuating around 2.2 Å in the last 2 ns. The final structure of the unbiased MD run was used as the initial structure of the targeted MD simulations. The target structure was obtained by setting each monomer to the state of the next functional rotating step, i.e., ABE→BEA.The whole system was equilibrated for 2 ns with the protein restrained by harmonic forces  is the instantaneous best-fit RMSD of the current coordinates to the target coordinates, *(t)RMSD is the preset RMSD value for the current time step, k is the force constant and N is the number of targeted atoms. The external forces were casted on all heavy atoms of AcrB. A tclForce script was used to perform mass-weighted targeted MD simulations. To assess the influence of parameters on the results, we performed a series of simulations using different force constants  and different simulation times (500 ps and 1 ns)  of the DBP is defined by all the atoms in the residues 628, 610, 136, 178, 615, 617, 277, 626, 620, 176, and 612 which lies in the vicinity of DBP:r(i) is the position of the ith atom, ω (i) is the mass weight and mcr is the weighted center of the selected atoms. The distance between Gln124 & Tyr758 is defined as the distance between the Cα atoms of the two residues. All data analysis and molecular structure visualization were conducted by VMD , or with two doxorubicins bound in the DBP of B monomer and in the PBP of A monomer, respectively (denoted as 2dox hereafter). Three parallel trajectories started with different initial velocities were produced for each system. The results were found to be insensitive to the selection of force constants or time lengths . During this period, the distance between residues Gln124 and Tyr758, which constrict the exit of drug extrusion  were also tested. These factors do not disturb the correlation between conformational changes in the DBP and substrate dissociation, either  to build the m Figure . The posm Figure . The prem Figure . Secondlm Figure . Finallym Figure . It is w Figures , so that2dox system was also earlier than that in the dox system. In the three trajectories, irreversible dissociation occurred at 200, 230, and 190 ps, respectively  concertedly, facilitating the unidirectional translocation of the substrate toward the outer membrane protein TolC. In this work, we simulated one functional rotating step of AcrB (ABE→BEA) in the context of one or two bound substrates using targeted MD simulations, and provided an atomic spatiotemporal view of the conformational changes and substrate movement.The targeted MD trajectories demonstrated that the simulation started with conformational changes in the translocation pathway, involving a set of concerted motions such as the closing of the PC1/PC2 cleft Figure , the shrThe functional rotating mechanism of AcrB assumes that the conformational transitions of the three monomers occur in a concerted way, implicating cooperativity in substrate translocation. Kinetic studies of substrate transport of AcrB in intact cells identified positive cooperativities in the efflux of various cephalosporins  transition  forms interactions with the TolC-docking domain and the subdomains PN2, PC1, and PC2 of the RND transporter. A noteworthy feature of the interactions between adaptor protein and RND transporter is that the subdomain PC2 forms much weaker contacts with the adaptor protein than PN2 and PC1 do. Only two residues on PC2 (Arg705 and Leu714) are located within 4 Å of the adaptor protein and they form weak van der Waals interactions. The binding of adaptor protein may restrain the motions in PN2 and PC1, but is less likely to disturb the motions of PC2 and the relative motions between PC1 and PC2. Since the second substrate in monomer A binds between the PC1 and PC2 subdomains, the adaptor protein may have little influence on the behavior of the second substrate and the accelerated conformational changes brought by its binding. The acceleration effects of AcrA-Mg2+ and multi-substrate binding may operate simultaneously when AcrB functions. It is worth noting, however, that the above notions are largely derived based on the static structures of CusBA and AcrAB-TolC complexes. Further studies, especially those concerning dynamic properties, are still required to provide a fuller understanding on the molecular mechanism of the acceleration effects.Although our simulation was conducted on isolated AcrB, the RND transporter functions together with the periplasmic adaptor protein AcrA and outer membrane protein TolC as a tripartite assembly, and AcrA-MgThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objective: The aim of the present study was to evaluate parameters of early blood flow (EBF) including duration of EBF, perfusion index (PI), uptake indexes 1 and 2 (UI1 and UI2) derived from dynamic thyroid scintigraphy in patients with Graves’ disease (GD), and euthyroid (EI). Maximum instant uptake and maximum uptake of the thyroid gland were also assessed.Methods: A total of 50 patients with GD and EI were included in this study. Each patient underwent two dynamic scans of 1-minute (20 images at 3 seconds) and 20-minute (20 images at 1 minute) with 99mTcO4. The time-activity curve of a 1-minute scan was employed to derive EBF parameters; likewise, the time-activity curve of a 20-minute scan was used to determine maximum instant uptake, and the gradient of the curve from the 10th to 20th minute was used to assess maximum uptake.Results: Values of EBF duration, PI, UI1, UI2, and maximum instant uptake were significantly lower in patients with GD than in those with EI (p<0.05). The calculated gradient of the second half of the curves for all of the patients ranged from 0 to 0.88 and was significantly higher in patients with GD than in those with EI.Conclusion: Lower values of PI, UI1, UI2 and durations of EBF, along with faster maximum instant uptake in patients with GD in comparison to EI are indicators of a heightened desire for hyper-functioning thyroid glands of patients with GD to absorb 99mTcO4. Additionally, because of the uprising gradient at the end of the 20-minute time-activity curve, a maximum thyroid uptake of 99mTcO4 was achieved at more than 20 minutes after the radiopharmaceutical injection. Various types of thyroid disorders may affect normal function of the thyroid glands. For instance, in Graves’ disease, thyroid stimulating hormone receptor antibodies (TSHR-Ab) bind thyroid stimulating hormone receptor (TSHR) and activate it, leading to hyper-secretion, hypertrophy, and hyperplasia of the thyroid follicles . One of 99mTcO4 with iodine (with respect to the molecular size), thyroid uptake of 99mTc can be used to assess thyroid function  and EI  were inc99mTcO4 as a bolus, thyroid scintigraphy of each patient was performed in the supine position with neck extended. A gamma camera  was positioned 7 cm over the thyroid gland. For each patient, dynamic scintigraphy was performed in two steps: first, in order to study perfusion of the thyroid gland, each patient was scanned over 1 minute as 20 frames of 3 seconds; second, in order to assess thyroid uptake, each patient was scanned over 20 minutes as 20 frames of 1 minute. Results of the scans were recorded on a 64×64 matrix using a zoom factor of 1.5.Following the intravenous injection 5 mCi Time-activity curves of the patients were generated following the background subtraction. In order to do this, one region of interest (ROI) was drawn around the thyroid gland to be used to determine thyroid activity while another ROI was drawn below the gland to be used to determine background activity.Parameters of thyroid blood flow were derived from time-activity curves similar to the method applied by Sekulic et al.  as folloEBF duration, which is the interval time between the start and the end of EBF curve; the perfusion index, which is the ratio of counts at the beginning of the EBF to the counts at the end of the EBF; the uptake index 1, which is the ratio of the counts at the end of EBF to the counts at the 60th seconds; and the uptake index 2, which is the ratio of the counts at the 30th seconds to the counts at the 60th seconds .99mTcO4 provides the required time for maximum uptake of the radiopharmaceutical, in a time-activity curve, the gradient of the line fitted to the second 10 minutes of the curve (from 10th to 20th minutes) was determined. Also, the time point during the 20-minute scans in which the highest amount of 99mTcO4 uptake would occur (maximum instant uptake) was determined for all patients with GD and EI  was used for the statistical analysis.99mTcO4. After the background subtraction, recorded activities were used to generate corresponding time-activity curves of the 1-minute and 20-minute scans.All of the patients with GD and EI underwent dynamic thyroid scintigraphy with 99mTcO4. A summary of the resulting data is presented in The 1-minute time-activity curves were used to extract semi-quantitative parameters of thyroid uptake of In the 20-minute time-activity curves, maximum instant gradient during 20 minutes for patients with GD and EI were determined as 4.30 and 5.54 minutes, respectively. According to the corresponding data, the time required for the thyroid to reach maximum instant gradient in patients with GD was significantly shorter than in those with EI (p<0.05).The gradient of the best-fit line to the curve from the 10th to 20th minute was calculated respectively as 0.125 and 0.0043 for the patients with GD and EI, indicating a statistically significant difference between the two groups (p<0.05) .In previous studies, it was found by ultrasonography that thyroid vascularity-and therefore thyroid blood flow-increased in patients with hyperthyroidism . In addi99mTcO4 scintigraphy has been reported in many studies . It was also found that uptake index 1 and 2 in patients with GD is faster than in those with EI, and the observed difference was statistically significant (p<0.05). These findings related to the increased vascularity and hyper-functioning thyroid glands in patients with GD were consistent with the results of a similar study performed by Sekulic et al.  of each generated time-activity curve indicated that, in the majority of patients with GD and EI, gradients of these lines were not zero and extended up to 0.88. The greater the gradient of the fitted line to the time-activity curve, the greater the tendency of the thyroid gland to reach its maximum uptake after 20 minutes. On the other hand, this semi-quantitative analysis indicated that static scintigraphy of the thyroid gland 20 minutes after the injection of 99mTcO4 might not accurately estimate thyroid function, and that a longer time interval might provide more reliable information. Comparison of the mean values of these gradients in patients with GD and EI revealed that this quantity is significantly higher in patients with GD than in those with EI. This means that patients with GD require much longer times than those with EI in order for maximum uptake to be achieved.As indicated in the literature and guidelines, thyroid glands achieve maximum uptake 20 minutes after the injection of 99mTcO4 in the earlier moments after the injection of the radiopharmaceutical and tends to absorb it for a longer time.Based on analysis of the gradients of the time-activity curve in each of 20 scans taken over 20 minutes (20 gradients for each curve), we also found that maximum instant uptake (among the 20 gradients for each curve) of thyroid gland occurs more quickly in patients with GD than in those with EI. The reason for our findings regarding maximum uptake and maximum instant uptake of thyroid might be related to the function of thyroid glands in patients with GD, in which the malfunctioned gland has more desire to absorb and keep 99mTcO4, we recommend that a duration longer than 20 minutes be considered between injection of the radiopharmaceutical and performance of the scintigraphy. However, further studies investigating dynamic scans of the thyroid gland at intervals greater than 20 minutes are recommended to support such an assumption.Thyroid glands of patients with GD, in comparison with those found in patients with EI, demonstrate faster UI1 and UI2, and maximum instant uptake occurs faster. In order to obtain more reliable statistical scans of thyroid glands with Conflicts of InterestThere are no conflicts of interest.


The above activity was evaluated by means of using the Fürst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented.Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their  Administering active substances into the skin constitutes a fundamental pathway of their application which has been known and used for many centuries in order to achieve local action. Because of its simplicity and convenience, this method can also be applied for a substance that can act in the inner parts of the skin or—by being absorbed into the blood—it can cause the systemic effect. However, this pathway is limited because only some substances can be transported through the skin. The substances can reach the deeper skin layers through the intercellular pathway or through the transcellular pathway (by penetration) .In order to improve the rate of transdermal penetration of drugs or cosmetics through the horny layer, physical, chemical and biochemical methods are used –8 such ae.g. oleic acid, lauric acid), fatty alcohols (e.g. 1-octanol), fatty acid esters (e.g. isopropyl mirystynate), amines and amides, sulfoxides and their analogues (e.g. DMSO), pyrrolidones (e.g. N-methyl-2-pyrrolidone [NMP] and 2-pyrrolidone), tenzides, lipids, laurocapram (Azone) and its derivatives, as well as terpenes and their derivatives m—mass of ointment applied on the membrane [g]in vitro in order to estimate their ability to penetration activity of a model therapeutic substance into a system of synthetic lipophilic membranes simulating the corneous skin layer. An analogous test was performed for the standard substance, Azone, for a comparison. The results are presented in Table 1.All of the obtained compounds containing the amide function at C-17 position were examined stratum corneum). In most cases the increased concentration of the triterpenic promoter caused better penetration of progesterone into these memebrane leyers. In general, alkalyne hydrolysis of the acetoxy function within the acetoxyamides led to compounds with lower activity as transdermal penetration promoters in comparison to the appropriate amides of acetyloleanolic acid. Introducing an additional 11-oxo function into the molecule of triterpenic amide did not have an influence on the total amount of progesterone that was absorbed into the set of five membranes.It was proven, on the basis of the conducted analyses of the dependence of the obtained compounds’ structure and their biological activity as transdermal delivery promoters, that replacing of the carboxylic group at C-17 position with the amide function led to a group of compounds of high activity. Almost all of the obtained compounds in both concentrations increased the total amount of the model substance in a set of artificial membranes simulating epidermis, particularly in the external part of this model , 4b, 5b (both with the N-methylpiperazine ring and the acetoxy or the hydroxy group at C-3 position), 4d  and 4f (having two nitrogen atoms within the amide function and the acetoxy group at C-3 position). Particularly active penetration promoters belonging to the group of oleanolic or acetylooleanolic acid amides turned out to be morpholides. Further activation of promoting activity of these compounds was performed by transforming of the C-3 hydroxy function, and the most active compound was seven-membered A-lactam.Our results proved that the most advantageous amide group positively influencing the total amount of progesterone absorbed in the whole system of lypophilic membranes were the N-methylpiperazine, the morpholine and the N,N-diethylamine moieties. A markedly increased amount of absorbed progesterone in all of the membranes, higher than in the case of applying of Azone, was observed for amides: 4a in a 1.0% concentration caused an over 40% increase in the progesterone amount in the external part of the human skin model (membranes 1–3). Two of the tested enhancers in a concentration of 0.5% (4b and 5b) and four derivatives in a concentration of 1.0%  caused an over 50% increase in the amount of the absorbed progesterone in the deeper parts of the stratum corneum model (membranes 4 and 5). Replacement of the C-3 hydroxyl group with the carbonyl or the hydroxyimino function as well as transformation of the last group into a lactam system resulted in better penetration of progesterone into the deeper membranes, with the best results for the compound with lactam system 12a (65.67% for membranes 4 and 5).Among the tested triterpenes, morpholide


The study group was divided into 4 subgroups: (I) patients with newly diagnosed type 1 diabetes, after an episode of ketoacidosis (n = 10), (II) patients with type 1 diabetes of duration no longer than 5 years (n = 9), (III) patients with 5 to 10 years of DT1 (n = 20), and (IV) patients with type 1 diabetes of duration longer than 10 years (n = 7). The concentrations of gastric peptide and adipocytokines across all subgroups were lower than in the control group. The differences were statistically significant (p < 0.0001), which may be of importance in the development of the disease complications. The increasing knowledge on the functions of gastric peptides and adipokines in the body allows the assumption of their major role linking the process of food intake, nutritional status, and body growth, largely through the regulation of glucose metabolism and insulin resistance. The aim of the study was the assessment of serum levels of selected gastric peptides and adipocytokines in children with type 1 diabetes, with respect to the disease duration. The study involved 80 children aged 4–18 years (M/F -37/43). Children with type 1 diabetes ( The increasing knowledge on the functions of intestinal peptides and adipokines in the body allows the assumption of their major role linking the process of food intake, nutritional status, and body growth, largely through the regulation of glucose metabolism and insulin resistance. The alimentary tract and human adipose tissue constitute an important part of the endocrine system, producing the greatest amounts of regulatory peptides. Food intake control is substantially regulated by the hypothalamic neurons that receive various signals from the so-called circuit-adipose tissue, stomach, intestines, thyroid, or pancreas , 2.One of the adipokines is omentin, a protein produced mainly in visceral adipose tissue. Its function is most likely to increase insulin sensitivity and stimulate glucose metabolism, and this effect can be both local and systemic. In vitro studies have demonstrated that omentin increases insulin sensitivity by stimulating insulin-dependent glucose uptake in both subcutaneous and visceral adipocytes . Since oAnother adipokine is apelin, which has been shown to enhance sensitivity of cells to insulin and delay the development of metabolic disorders associated with obesity , to a laGhrelin and obestatin are hormones secreted by the digestive tract, mainly the parietal cells of the gastric fundus . They haMost papers evaluating the relationship of gastrointestinal peptides and adipocytokines with glucose metabolism provide data obtained from studies conducted on animal models or adults with type 2 diabetes. There are only few reports assessing these relationships in young patients with type 1 diabetes.Aim of the Study. The study objective was to evaluate the concentrations of selected gastric peptides and adipocytokines in blood serum of children with type 1 diabetes, taking into account the disease duration.n = 10), (II) patients with type 1 diabetes of duration no longer than 5 years (n = 9), (III) patients with 5 to 10 years of DT1 (n = 20), and (IV) patients with type 1 diabetes of duration longer than 10 years (n = 7).The study included 80 children aged 4–18 years (M/F -37/43), diabetic patients of Diabetology Outpatient Clinic and Department of Pediatrics, Endocrinology, Diabetology with Subdivision of Cardiology, Medical University of Bialystok. The group of 46 children with type 1 diabetes (diagnosed by ISPAD criteria) was compared to the control group of 34 healthy children with a negative history of inflammatory diseases, autoimmune diseases, or cancer. For the purpose of the study, the diabetic group was divided into 4 subgroups: (I) patients with newly diagnosed type 1 diabetes, after an episode of ketoacidosis  using standard methods, as well as ghrelin, apelin, and omentin-1, and obestatin measured by ELISA. Statistical analysis was performed using Statistica 10.0. The nonparametric Mann-Whitney p < 0.0001)  . Moreove 0.0001) .The glycated hemoglobin level was the highest in subgroup I (10.1%), due to the fact that these were recently diagnosed cases of type 1 diabetes. The mean HbA1c among children in the subgroups II and III were comparable (6.9% vs. 7.6%). Higher HbA1c (8.7%) was observed in the group of children with the longest disease duration and thus with the lowest level of the peptides tested .p = 0.029) and had a statistically significantly lower body weight (p = 0.028) as compared to the control group, whereas patients with the longest disease duration and the lowest levels of the substances tested had a higher BMI than healthy children (p = 0.027)  .Moreover, we noted a statistically significant negative correlation between BMI and the levels of all the regulatory substances tested, between body weight and the levels of obestatin, ghrelin, and apelin in children with the longest disease duration and between BMI and the concentrations of obestatin and apelin in children with 5 to 10 years' lasting diabetes.Hormones secreted by the digestive tract and adipose tissue are important regulators of energy metabolism. Numerous studies concerning different fields of medicine are still discovering their novel properties. Hormones are involved in many biological processes which affect not only the function of the gastrointestinal tract but also endocrine and immune systems, the processes of growth and maturation. Accurate knowledge of the mechanisms of regulatory peptides and factors that influence their release may create new possibilities not only in the treatment of obesity and inflammatory diseases but also in the treatment of type 1 diabetes.The results of the present analysis show a negative correlation of regulatory peptides with body mass and BMI. Similar correlations were observed in a study conducted by Tapan et al., showing significantly lower plasma apelin concentration in obese children as compared to children with normal weight . ReportsOur analysis indicates that the lower levels of regulatory substances are accompanied by a higher BMI and increased glycated hemoglobin. However, there are reports in which positive correlation was observed between apelin level and body mass index (BMI), HOMA-IR, triglycerides, glucose, and glycated hemoglobin (HbA1c) . HoweverIn the present analysis, a subgroup of patients with the longest duration of the disease had the lowest levels of the peptides tested. The available data indicate that apart from numerous known actions of the digestive hormones and adipocytokines, there are others that affect proliferation and survival of pancreatic isles cells , which mInsulin resistance affects the clinical course and metabolic control in patients with both type 2 and type 1 diabetes. In children with type 1 diabetes, insulin resistance is higher than in the group of their peers . The avaA significantly higher than normal risk of developing atherosclerosis in diabetic patients can be explained by a higher incidence of classical risk factors for developing cardiovascular diseases in these patients, adverse effects of diabetes on other risk factors, such as dyslipidemia and hypertension, and the direct effect of hyperglycemia or diabetes itself , 21. CarThe differences detected in the study population encourage a more detailed analysis of the observed correlations and a potential contribution of these substances to the development and course of type 1 diabetes.To conclude it should be stated that the peptides of the gastrointestinal tract and adipokines can modulate insulin sensitivity not only in healthy individuals but also in patients with pancreatic dysfunction. Their concentration not only affects the occurrence of hypo- and hyperglycemia , but aboBased on data obtained from animal studies and adults with type 2 diabetes it seems that the lower concentrations of gastrointestinal peptides and adipocytokines are responsible for lower insulin sensitivity and glucose metabolism in comparison with the general population. Further research into the correlation observed should be performed on a larger group of patients, to specify the role of these substances in the course of type 1 diabetes.The levels of gastric peptides and adipocytokines are higher in patients with normal renal secretion of the pancreas than in patients with type 1 diabetes, which may be important in the development of complications in the course of this disease entity.The disease duration, HbA1c, and BMI can affect the levels of the regulatory peptides in the body.


In order to guarantee the stable operation of shearers and promote construction of an automatic coal mining working face, an online cutting pattern recognition method with high accuracy and speed based on Improved Ensemble Empirical Mode Decomposition (IEEMD) and Probabilistic Neural Network (PNN) is proposed. An industrial microphone is installed on the shearer and the cutting sound is collected as the recognition criterion to overcome the disadvantages of giant size, contact measurement and low identification rate of traditional detectors. To avoid end-point effects and get rid of undesirable intrinsic mode function (IMF) components in the initial signal, IEEMD is conducted on the sound. The end-point continuation based on the practical storage data is performed first to overcome the end-point effect. Next the average correlation coefficient, which is calculated by the correlation of the first IMF with others, is introduced to select essential IMFs. Then the energy and standard deviation of the reminder IMFs are extracted as features and PNN is applied to classify the cutting patterns. Finally, a simulation example, with an accuracy of 92.67%, and an industrial application prove the efficiency and correctness of the proposed method. Nowadays, cutting pattern recognition for shearers, which aims at determining whether the shearer is cutting coal or rock, plays an important role in increasing coal output and avoiding cutting hard rock in fully-mechanized coal mining working faces. However, due to the poor working conditions during the production process, online cutting pattern recognition is always a tough technical problem . Since tet al., in 1998 etc. The al field , a new a T, and the vector can be classified into one of the c categories. The neuron number of input layer is identical to the dimension of x, the input layer takes charge of receiving and transporting the test samples. There exist c groups of neurons in the model layer, where each group corresponds to a category. The neuron number of each group is equal to the test sample amount of the corresponding category, and each neuron connects to the input layer completely. The output of j-th neuron in i-th group can be expressed as follows:i = 1, 2…c, j = 1, 2… iN, iN is the sample number of i-th group, σ is the smooth factor, j-th training sample of category ωi. In summation layer, there are c nodes, and each node connects to the homologous neuron in model layer. The result of i-th node can be calculated as follows:The Probabilistic Neural Network (PNN) is a supervised feed-forward neural network that is widely applied in the field of pattern recognition. A typical PNN contains input layer, model layer, summation layer and output layer. It is assumed that a P(ωi) is the prior probability of i-th category. For the input vector x, if i ≠ j N sample sound series in different cutting patterns and divide them into N1 training data and N2 testing data.Acquire (2)N series and decompose them into several IMF components. Then eliminate the continuation data and select essential IMF components. The selection process is confirmed by the relationship between the average correlation coefficients and the redundancy threshold ξ.Extend the (3)N1 training series into the initial PNN, and the cutting pattern is the output of PNN.Extract the energy and standard deviation of the reminder IMFs as features, and normalize the feature vector of the sound series. Input the extracted vectors of (4)Input the feature vectors of the testing series into the trained PNN, and acquire the cutting pattern of each testing sample finally. The flowchart of cutting pattern recognition method can be shown in According to the end-point extension and average correlation coefficients, an online cutting pattern recognition approach through the cutting sound based on IEEMD and PNN can be presented as follows:In this section, a simulation example is put forward to verify the efficiency and correctness of the proposed method. Sound of five different kinds of cutting pattern was collected, respectively. Then IEEMD, feature extraction and PNN classification processing were performed in order. Some comparison and analysis were conducted according to the simulation example.L = 22.05 × 103) were collected. Half (300 series) were treated as the training samples and the remaining 300 series were the testing samples.The sample data were acquired from the National Coal Mining Equipment Research and Experiment Center at the China Coal Zhangjiakou Coal Mining Machinery Co., Ltd. A 70 m long cutting wall, with the height of 1.2 m, was built to simulate real geological conditions, and the shearer model was an MG500/1130-WD. The cutting wall contained four sections: a 20 m long pure coal seam with a Protodikonov hardness coefficient of f2 (C1), a 20 m long pure coal seam with a hardness of f3 (C2), a 15 m long pure hard rock seam (C3) and a 15 m long coal seam including rocks (C4). The traction speed of the shearer was a constant 3 m/min and the cutting drum rotate speed was 25 r/min. An industrial microphone was utilized to record the cutting sound of C1, C2, C3, C4 and the condition with no-load (C5), as shown in l was set as 100. Then the standard EEMD was conducted and the extended parts were eliminated subsequently, where the result of C1 is shown in The cutting sound of the shearer for different cutting patterns was decomposed according to the IEEMD. The initial data series of the training samples is shown in Tmax was 14, so an arbitrary signal mX can be described by Equation (14) and zero vectors were supplemented in low frequency for series without Tmax IMFs.m,tIMF was t-th IMF component of m-th sound series, m = 1, 2, 3... 600.After decomposing 600 sound series, the biggest IMF component number The average correlation coefficients of the training series were calculated and are listed in ixb, a], the normalization process could be shown as follows:b was maximum value of ix, a was minimum value and Nix was the normalized value of ix.The IEEMD eliminated undesirable IMF components from the original sound signal according to the redundant threshold ξ. The energy and standard deviation of the remainder IMFs were extracted as the features according to Equation (9). In order to facilitate computation and training of the PNN, normalization was operated subsequently. For an arbitrary After normalizing the energy and standard deviation of the eight IMFs, a 16-dimensional vector was obtained according to Equation (10). The 16 elements were organized as the feature vectors representing each sound series and all 600 feature vectors are shown in The initial PNN was trained with the 300 training series, where the inputs of the network were the extracted vectors and the outputs were the corresponding cutting patterns. The node number of the input layer was 16, and there were five groups of nodes in the model layer, where each group contained 60 training samples. Obviously, five nodes corresponding to the cutting patterns existed in the summation layer, and the output of the PNN was one of C1, C2, C3, C4 and C5. The smoothing factor σ in the PNN was 0.1, the prior probability of each category was 1/5 in the model layer and the iteration number was set as 1000. Then testing samples were treated by the trained PNN and comparison was made between the actual cutting pattern and PNN prediction results, as shown in Seen from Finally, to obtain the change rule of the reminder IMF number and the prediction accuracy at different redundancies, seven thresholds were selected and compared according to the distribution rule of the average correlation coefficients, and the results are shown in In In order to demonstrate the superiority of the proposed method to those proposed by other similar researchers, a comparison and analysis was presented in this paper. According to the relevant literature, natural γ-ray detection, WPT and PNN, traditional EEMD and PNN, and the improved method in  were selIn this section, an online system based on the proposed method had been developed and applied in the field of automatic coal mining as shown in In order to realize online cutting pattern recognition during coal mining, this paper proposes a novel approach using the cutting sound based on an improved EEMD and PNN. Improved strategies on the basis of end-point continuation and correlation of IMF1 with other IMF components were applied in EEMD to avoid end-point effects and eliminate undesirable IMF components, and then PNN was used as the classification algorithm. To verify the feasibility and superiority of the proposed approach, a simulation example was provided and some comparisons were conducted. The simulation example and comparison results showed that the online cutting pattern recognition method could effectively distinguish the cutting pattern and the proposed approach outperformed others.However, there are also some limitations and bugs in this method that may be listed as follows: (1) The redundant threshold of the average correlation coefficient is selected by extensive simulations. Strict mathematical derivation is absent in the process, which increases blindness of the recognition system; (2) the traction speed of the shearer is a constant 3 m/min, which does not match the changing practical conditions; (3) the online system still has the problem of response delay in the present model. In future studies, the authors plan to investigate some improvements to the proposed approach. These may include an adaptive algorithm to select an appropriate redundant threshold, a cutting pattern recognition method for changing cutting speeds and higher execution efficiency of the algorithm code.


A parametric study of nonlinear seismic response analysis of transmission line structures subjected to earthquake loading is studied in this paper. The transmission lines are modeled by cable element which accounts for the nonlinearity of the cable based on a real project. Nonuniform ground motions are generated using a stochastic approach based on random vibration analysis. The effects of multicomponent ground motions, correlations among multicomponent ground motions, wave travel, coherency loss, and local site on the responses of the cables are investigated using nonlinear time history analysis method, respectively. The results show the multicomponent seismic excitations should be considered, but the correlations among multicomponent ground motions could be neglected. The wave passage effect has a significant influence on the responses of the cables. The change of the degree of coherency loss has little influence on the response of the cables, but the responses of the cables are affected significantly by the effect of coherency loss. The responses of the cables change little with the degree of the difference of site condition changing. The effect of multicomponent ground motions, wave passage, coherency loss, and local site should be considered for the seismic design of the transmission line structures. Transmission line structures are very important to electric engineering. Most of the transmission lines cross the highly seismic region. The past earthquakes indicate that transmission lines are often damaged under earthquake loading. About 100 transmission lines of Los Angeles city were destroyed in the 1992 Landers earthquake . A lot oMost of research has focused on the actions of static load, impulsive load, and equivalent static wind load. There are no calculation methods about how to consider the transmission line structures under earthquake loading in current seismic codes , 5. SomeWith the development of techniques, the spans of transmission lines have increased dramatically. It is unrealistic to assume that earthquake ground motions for long span transmission tower-line system are the same and single component. Ghobarah et al.  investigThe parametric studies of seismic response analysis of transmission line structures considering geometric nonlinearity subjected to earthquake loading are carried out in this paper. The transmission lines are modeled by cable element account for the nonlinearity of the cable based on a real project. The effects of multicomponent ground motions, correlations among multicomponent ground motions, wave travel, coherency loss, and local site on the responses of the cables are investigated using nonlinear time history analysis method, respectively. The analysis results could provide reference for the seismic design of the transmission line structures.A typical three-dimensional finite element model of transmission line structures is established based on a real electric project in the north of China. SAP2000 finite element program is used to simulate the transmission line structures. As shown in α = sinh−1|β(c/l)/sin(β)| + β, β = ql/2H, H represents the initial horizontal tension which can be obtained from a preliminary static analysis, and q denotes the uniformly distributed gravity loads along the conductor and ground lines.Under self-weight, the cables' configuration is a catenary. Based on the coordinate system illustrated in i and j isdij is the projected distance in the wave propagation direction between points i and j in the wave propagation direction, β is a constant, and a(ω) is a function with the forma, b, and c can be obtained by least-squares fitting the coherency function of recorded motions. The constants in coherency function are a = 3.583 × 10−3, b = −1.811 × 10−5, c = 1.177 × 10−4, and β = 1.019 × 10−4, which were obtained by processing recorded motions during Event 45 at the SMART-1 array [An empirical coherency loss function derived from SMART-1 array is used in the paper . The coh-1 array , and it A stochastic approach based on random vibration analysis is used, and the simulated ground motion time history is iterated to be compatible with the response spectrum defined in Code for Design of Seismic of Electrical Installations. Reference  gives thThe parametric studies of nonlinear seismic responses of the transmission line structures under earthquake loading are analyzed using nonlinear time history analysis method. The geometric nonlinearity is taken into account due to large deformation of the transmission lines. The HHT (Hilber-Hughes-Taylor) method is applied in the numerical integration. The layers of cables shown in To study the effect of multicomponent ground motions, three typical natural seismic waves are selected, which are El Centro wave, Oka wave, and Taft wave. The selection of seismic waves is shown in Four cases are considered, longitudinal excitation only (Case 1), transverse excitation only (Case 2), vertical excitation only (Case 3), and multicomponent excitations (Case 4). Case 1 is longitudinal excitation only, and the horizontal 1 component of the seismic wave is inputted along longitudinal direction of the transmission line structures model. Case 2 is transverse excitation only, and the horizontal 2 component of the seismic wave is inputted along transverse direction of the transmission line structures model. Case 3 is vertical excitation only, and the vertical component of the seismic wave is inputted along vertical direction of the transmission line structures model. Case 4 is multicomponent excitations, and the horizontal 1, horizontal 2, and vertical component of seismic wave are inputted together along longitudinal, transverse, and vertical direction of the transmission line structures model, respectively.The maximum value curves of the vertical displacements of the cable under different analysis cases are shown in α = 0° (Case 2), α = 18° (Case 3), and α = 45° (Case 4). The correlations among multicomponent ground motions are selected based on previous studies [To research the effect of the correlations among multicomponent ground motions, four cases are considered, uniform (Case 1),  studies .The maximum values of the tension forces of the cables under different degrees of the coherence are shown in To investigate the effect of ground motion spatial variations, four cases are considered, uniform (Case 1), wave passage effect only (Case 2), coherency loss effect only (Case 3), and local site effect only (Case 4). Case 1 is the uniform excitation, because the apparent velocity, coherency loss, and soil condition of ground motion are assumed to be infinite, highly correlated, and mid-firm site, respectively.The maximum value curves of the vertical displacements of the cable under different analysis cases are shown in To study the effect of apparent velocity, ten different velocities of wave propagation are considered in the analysis, uniform (Case 1), 200 m/s (Case 2), 400 m/s (Case 3), 600 m/s (Case 4), 800 m/s (Case 5), 1000 m/s (Case 6), 1200 m/s (Case 7), 1600 m/s (Case 8), 2000 m/s (Case 9), and 3000 m/s (Case 10), to cover the range of practical propagation velocities in engineering. In all these cases, the coherency loss and soil condition of ground motion are assumed to be highly correlated and the mid-firm site, respectively.The maximum value curves of the vertical displacements of the cable under different traveling wave velocities are shown in The maximum value curves of tension forces of the cables under different traveling wave velocities are shown in Based on the variations of the displacements and tension forces of the cables considering the change of traveling wave velocity, the wave travel effect has a significant influence on the response of the cables. The vertical displacements of the cable are amplified greatly considering the wave travel effect. The vibration of the cable is very large, which would lead to discharge and short circuit. The tension forces of the cables considering the wave travel effect are larger than that of under uniform excitation. Because the tension forces of the cables are too large, the transmission lines would be pulled off and the situations usually occur in the past earthquakes. Therefore, it is necessary to estimate the traveling wave velocity accurately.To investigate the effect of coherency loss, uniform (Case 1), uncorrelated (Case 2), weakly (Case 3), intermediately (Case 4), highly (Case 5), and completely correlated (Case 6) ground motions are considered, respectively. It should be noted that the correlation as low as uncorrelated does not usually occur at short distances, unless there are considerable changes in the local geology from one support to the other. In all these cases, the apparent velocity and soil condition of ground motion are assumed to be 1000 m/s and the mid-firm site, respectively.The maximum value curves of the vertical displacements of the cable under different degrees of coherency loss are shown in The maximum value curves of tension forces of the cables under different degrees of coherency loss are shown in The variations of the displacement and force responses of the cables considering the change of coherency loss can be obtained from the above analysis. The vertical displacements of the cable have an increasing tendency with the decrease of the degree of coherency loss. The change of coherency loss can be ignored, but the effect of coherency loss must be considered. Therefore, it is very important to consider the coherency loss effect of ground motion for the seismic design of the transmission line structures.To research the effect of local site influence on the cable responses, eight cases are considered, Case 1~Case 8. Analysis cases considering the effect of local site are shown in The maximum value curves of the vertical displacements of the cable under different site conditions are shown in The maximum value curves of tension forces of the cables under different site conditions are shown in Based on the above analysis, the variations of the displacement and tension force responses of the cables considering different site conditions can be summarized. The vertical displacements and tension forces of the cable have an increasing tendency with the site condition growing soft. The responses of the cables change little with the degree of the difference of site condition changing, especially for the tension forces of the cables. Therefore, the local site effect should be considered for the seismic design of the transmission line structures.The vertical displacements of the cable under multicomponent excitations are significantly larger than that of under vertical, longitudinal, or transverse excitation only. Multicomponent seismic excitations should be considered.Ignoring the correlations among the multicomponent ground motions, the response of the cable may be small, but the changes are very little. The correlations among multicomponent ground motions can be neglected.The responses of the cables considering the effect of ground motion spatial variations are larger than that of under uniform excitation. Wave travel effect of ground motion is more obvious to the influence of the structure than the other effect for the flexible structure of the transmission line structures.The wave passage effect has a significant influence on the responses of the cables. Neglecting the wave passage effect in analysis, the cables responses would be underestimated. Because the tension forces of the cables are too large, the transmission lines would be pulled off. It is necessary to estimate the traveling wave velocity accurately.The change of the degree of coherency loss has little influence on the response of the cables. The responses of the cables are affected significantly by the effect of coherency loss. It is very important to consider the coherency loss effect of ground motion for the seismic design of the transmission line structures.The vertical displacements and tension forces of the cables have an increasing tendency with the site condition growing soft. The responses of the cables change little with the degree of the difference of site condition changing, especially for the tension forces.The parametric studies of nonlinear dynamic responses of the transmission line structures subjected to earthquake loading are investigated in the paper. The effects of multicomponent ground motions, correlations among multicomponent ground motions, ground motion spatial variation, wave passage, coherency loss, and local site on the transmission line structures are considered, respectively. Based on the numerical results, the following conclusions are drawn.


The paper describes echocardiographic values of systolic and diastolic dysfunction the right heart ventricle in 229 patients with chronic obstructive pulmonary disease. In our patients the values AvPAP (≥25 mmHg while resting), FDDrv and FSDrv (>26 and 20 mm respectively), the thickness of front wall the RV (>5 mm), the dimension of AD (>35 mm), as well as the reduction the vestibular-distal shortening of RV (<23%), maximum blood velocity and the blood evacuation time from reflect indirectly the progressive reduction the contractive capacity RV myocardium and the occurrence of systolic dysfunction. In patients with severe de-compensation a restrictive type diastolic function is more characteristic – acceleration of early diastolic filling and blood velocity decrease during the auricular systole. Currently there is a commonly known hypothesis explaining the progressive character of the remodeling and formation of the chronic heart failure (CHF) being the neuro-hormonal heart failure model , and staThe purpose of the present paper was to detect the formation of chronic cor pulmonale in patients with COPD, living in the Central Area of Sakha Republic (Yakutia) .The basis of this part of the paper was formed by the results of clinical lab and instrumental examination of 229 COPD patients, in cases of complicated CCP.1). This, for all examined patients a combination of bronchial obstructive syndrome and lesions of respiratory pulmonary segments. Partially (124 cases), signs of decompensated CCP and PAH  were evident.COPD was determined after generally accepted criteria  based onThus, the main inclusion criteria of the patients in this part of the investigation were:1)Available trustworthy clinical and instrumental signs of COPD ;2)FEP1/FVCL less than 70% of the norm;3)Patient’s informed consent.The severity of the disease was determined after GOLD classification, rev. 2013The diagnostic criteria of chronic cor pulmonale were:1)Generally accepted clinical and instrumental signs of RV hypertrophy and/or widening of the hollow of RV and AD;2)Echocardiographic signs of AvPAP increase >20 mmHg;3)Clinical signs of blood congestion in the greater circulation ;4)Echocardiographic signs of systolic dysfunction of RV.It should be underlined, that in each particular case the clinical and instrumental diagnosis of CCP was based on meeting of 2 or more criteria, as described above.The exemption criteria of patients from the group were:Distinct signs of bronchospasm and frequent asphyxia attacks in patients with accompanying bronchial asthma.Detection of acute MI or unstable angina pectoris.The clinical and instrumental examination of COPD and CCP patients was conducted during the period of COPD relevant emission and in absence of the intensification of the inflammation process in the lungs and bronchi.st group was formed by 105 COPD patients without trustworthy signs of CCP. The 2nd group comprised 71 COPD patients with compensated CCP signs. The 3rd group included 53 patients with de-compensated CCP and CHF of RV signs.All patients were divided into 3 groups. The 1The data obtained were statistically processed.The echocardiography was performed with the echocardiographic unit “Acuson-128 XP” (USA). The instrument ensures ultrasonic investigation in 2D and M-Mode, as well as the Doppler investigation of the blood flux in pulse and constant wave modes. The investigation was arranged after a generally accepted method using the left parasternal, apical and subcostal accesses.The investigation was conducted simultaneously with ECG recording to synchronize the phases of the heart cycle of the echocardiogram with the ECG data. The wall thickness and heart hollows dimension measurement in systolic and diastolic phases were conducted in accordance with the method of the American Experts Committee on Echocardiography. The residual volumes of the left ventricle (FDV and FSV), the stroke volume (SV) and the discharge fraction (DF) were calculated after Simpson. The average pressure of the PA (AvPAP) was determined after A. Kitabatake (1983), whereas the quantitative parameters of the systolic blood flow in the outlet segment of the RV were measured and the flow acceleration time (AcT) to the total duration of the expulsion from RV (RVET) was calculated.The diastolic function of the RV and LV were evaluated after the results of the Doppler measurement, accordingly, of those of trans tricuspid and transmission diastolic blood flow in pulse, color and constant wave modes.st group  only a statistically non-trustworthy tendency (p>0.05) to a slight increase of the AvPAP is observed as compared with the reference group patients. A statistically significant increase of this hemodynamic parameter was detected only in the patients of the 2nd and the 3rd group with verified CCP (p <0.001). Thereby the AvPAP level in the patients of the 3rd group with de-compensated CCP proved in general to be higher than in CCP patients of the 2nd group without CHF signs (p <0.05). Nevertheless, the pressure increase of the PA in the patients of the 2nd and the 3rd group was moderate, and in never exceeded 22.6±1.2 and 27, 4±1.2 mmHg, respectively.nd group (26.8%) and 5 patients of the 3rd group (9.4%) had the PA pressure level less than 20 mmHg. On the other hand, 16 patients of the 1st group without CCP signs (15.2%) the AvPAP value appeared to be higher than the stated threshold value. Thus, a direct dependence of presence or absence of cor pulmonale upon the AvPAP value measured while resting was not detected in many cases.The analysis of individual AvPAP values demonstrated that the most patients with verified CCP have values of this hemodynamic parameter in exceed of 20 mmHg. Simultaneously, it should be underlined that 19 of 71 patients of the 2rd group with de-compensated CCP.In assessment of these results one can assume that the PA average pressure value, measured in CCP patients only when they are resting, is far from precise demonstration of the increase extent of the pulmonary vessel resistance and the intensity of the relevant alterations in the heart muscle. It should be taken into account that the PA pressure level is to a certain extent dependent on the magnitude of the contractive capacity and the diastolic volume of the RV, presence or absence of tricuspid regurgitation, on the pre-tension of the RV and some other hemodynamic parameters , the latfront wall thickness of the RV (FWTrv). In our paper, as well as in works of other authors, as a criterion of a diagnostically significant FWT growth of the RV the values >5 mm were taken. The average FWTrv value in the patients of the 1st group made up 4,62±0.2 mm, trustworthily different (p<0.05) from the relevant value in the reference group patients (3.86±0.3 mm), thus demonstrating a distinct tendency to myocardial mass growth of the PV long before the appearance of trustworthy cor pulmonale signs. Moreover, in 12 of 105 patients of the 1st group (11.4%) FWTrv appeared greater than 5.0 mm. Nevertheless, it did not get a reason to assign the patients to the group with compensated CCP (2nd group) in connection with the fact, that in accordance with the applied algorithm a diagnosis of RVH was considered probable only in case of compliance with all 3 clinical and instrumental criteria of CCP stated above.The second most important sign typical for CCP patients is the growth of the nd (p<0.05) and especially of the 3rd group (p<0.001), whose average values of this parameter made up accordingly 5.29±0.2 mm and 5.80±0.2 mm. Nevertheless, in 11 patients of the 2nd group (10.5%) and 3 patients of the 3rd group (5.6%) the values of FWTrv did not exceed 4.8 mm, and the diagnosis CCP was stated based on other clinical and echocardiographic signs of cor pulmonale (see below).Trustworthy differences of FWTrv from the norm were detected in the patients of the 2the final-systolic (FSDrv) and final-diastolic (FDDrv) dimension of the RV. In COPD patients without CCP signs (1st group) both systolic and diastolic dimensions do not trustworthily differ from those in the reference group patients (p<0.05), whereas in the patients of the 2nd group with verified CCP moderate but statistically significant increase of FDDrv and FSDrv (p<0.001). In most cases of compensated CCP the values of these two parameters exceeded accordingly 22.0 and 15.0 ml, whereas in the patients of the 1st group they appeared to be less than these values (p<0.001). The moderate increase of the dimensions of the RV in the patients of the 2nd group is obviously stipulated by the effect of the compensatory mechanism of Frank-Starling, directed to the retaining of the stroke volume of the RV and the heart discharge. The proof for this is the absence in such patients of a trustworthy decrease of the parameter ΔS% RV (28.2±2.4%), which did not differ from that both in the patients of the reference group (31.7±2.5%), and in COPD patients of the 1st group (30.5±2.3%). Simultaneously a rather high maximum blood flow velocity in the PA (PV Vmax) was retained, as well as the normal duration of the expulsion time of the RV (RVET).A number of principal parameters reflecting the heart re-modeling process in COPD patients, are rd group was accompanied by a still higher growth of FDDrv and FSDrv (p <0.001), which almost in all cases exceeded accordingly 26.0 and 20.0 mm. Thereby in patients with de-compensated CCP both diastolic and systolic RV dimension correlated in general well with the intensity of CHF. Simultaneously, in these patients a trustworthy decrease of ΔS% RV  was registered, as well as the maximum blood flow velocity (PV Vmax) and the expulsion time (RVET), indirectly reflecting the progressive decrease of the contractive capacity of the RV and the onset of RV systolic function.The CCP de-compensation in the patients of the 3cor pulmonale marker than AvPAP and the front wall thickness of the RV. One should consider that technically the measurement of FDDrv and FSDrv is simpler than the calculation of the PA pressure and the measurement of FWTrv.Thus, in the overwhelming majority of the cases the systolic and the diastolic RV dimensions grew in the COPD patients only when CCP was getting shape. It should be noted that the RV dimensions were even more trustworthy and reliable The relative RV front wall thickness index calculated as the proportion FWTrv vs. FDDrv (H/D) did not differ in the patients of the 2nd group (0.19±0.01) from that of the reference group (0.20±0.01) and that of the 1st group of COPD patients (0.19±0.01), being together with the trustworthy increase of the absolute FWTrv values an evidence of prevailing concentric hypertrophy signs in the 2nd group.rd group with de-compensated CCP, in spite of the further myocardial mass growth of the RV, a statistically not trustworthy (p>0.05) tendency to the decreasing of this parameter (0.17±0.02) was observed, being an evidence of mostly eccentric RVH development in such patients.In the patients of the 3atrium dextrum (AD) in the COPD patients. As shown in st group the FDD AD value differed only slightly from the norm (p >0.05), although a not trustworthy tendency to a certain growth of this parameter as compared to the reference group (28.7±1.4 mm) was observed. More significant the AD dimension (33.0±1.2 mm) was in the patients with compensated CCP (p <0.001) what partially could be associated with the increase of the RV filling pressure, typical for patients with distinct compensatory hypertrophy of the RV and its diastolic dysfunction (see below). Thus, on the initial stage of cor pulmonale shaping, the increase of the AD dimensions was mostly of compensatory type reflecting the increase of the auricular pumping function.It is well-known that for a normal pumping function of the ventricles the function of the atria is important. In this connection we studied the state of rd group) a greater dilatation of the AD (37.2±1.6 mm) was observed, the latter mostly stipulated by the growth of the central venous pressure (CVP) on the background of the progressive systolic and diastolic dysfunction of the RV. Of importance was also the frequent detection in these patients of the relative tricuspid valve insufficiency which was characteristic for patients with systolic ventricle dysfunction. In the patients of the 3rd group structural changes of the right heart compartments (atrium and ventricle) were connected to one another, the evidence for it is a slight but trustworthy interaction between FDD AD and RV hollow dimension , as well as its wall thickness .In patients with de-compensated CCP . The frequency of the tricuspid regurgitation was higher in de-compensated CCP patients (14 persons or 26.4%). In the patients of the 2nd group the tricuspid valve insufficiency was detected only in 5 cases (7.0%). The difference is statistically trustworthy (p <0.05). For clear reasons, in the 3rd group patients there was also a greater average extent if tricuspid regurgitation (2.46±0.7 vs. 1.32±0.5 st. in the patients of the 2nd group), although statistically the difference was insignificant (p >0.05).st group a not trustworthy lowering of the amplitude of the E-peak and a statistically significant (p<0.05) increase of the A-peak height were observed. In this connection the E/A proportion in the patients of the 1st group trustworthily decreased (p<0.001). Simultaneously an increase of the time (p<0.001) of the isovoluminal RV relaxation (IVRT) and the slow-down time of the early diastolic filling (DT) were registered.In the Doppler diagrams of the transtricuspid blood flow in the patients of the 1nd group) such changes were still more distinct: the IVRT duration reached 116.3±2.6 ms, DT – 226±3.5 ms, and the E/A proportion – 1.05±0.02 (p<0.001), that is, trustworthily different from the average values of the same parameters in the patients of the 1st group (p<0.01).In patients with compensated CCP (2In patients with distinct signs of heart failure and increased pressure gradient from atria to ventricles during the rapid filling phase the transformation of Type I of the diastolic dysfunction of the RV to Type II (restrictive), with distinguishing significant acceleration of the early diastolic filling of the ventricle (Peak E) and simultaneous decreased blood flow velocity during the systole of the atrium (Peak A). Thereby the proportion E/A increased, the phase of the isovoluminal relaxation was reduced (IVRT), as well as the slow-down time of the early diastolic filling (DT).rd group moderate but trustworthy increase of the average values of Peak E  and E/A  and decrease of Peak A , of IVRT , and DT  were observed, reflecting a more distinct tendency to the generation of the restrictive type of the diastolic dysfunction of the RV, commonly known as the evidence of an essential increase of the ventricle filling pressure and considered to be rather unfavorable in terms of prognosis.As a result, in general, in the 31)In the earliest stages of morphological and functional heart remodeling, long before the manifestation of commonly known signs of CCP (hypertrophy and/or dilatation of the RV), in COPD patients moderate abnormality of the diastolic function of the RV of Type I (slowed-down relaxation) and the increase of the RV front wall thickness are observed, not reaching the diagnostically significant level (5.0 mm). In this stage of CCP generation in COPD patients only a not trustworthy tendency to increased AvPAP while resting, and AD (p >0.1) is observed.2)The shaping out of compensated CCP (in the patients of the 2nd group) is generally characterized by a trustworthy growth of AvPAP (>20 mmHg), the growth of the front wall of the RV (>5 mm), as well as the growth of the diastolic and systolic dimensions of the RV hollow (>22 mm and 15 mm respectively) whereas normal values of the relative front wall thickness index (H/D) are retained.3)The de-compensation of CCP and the development of RV CHF is accompanied by a still greater increase of AvPAP (≥25 mmHg while resting), of FDDrv and FSDrv (>26 mm and 20 mm respectively), of the RV front wall thickness (>5 mm), of AD (>35 mm), as well as by the reduction of the extent of the vestibular-distal RV shortening (ΔS %) (<23%), of the maximum blood flow velocity (PV Vmax), and the duration of the expulsion period of blood from the RV (RVET), being an indirect evidence of the progressive reduction of the myocardial contractive capacity of the RV and the onset of its systolic dysfunction.


Isolated trigonocephaly is a nonsyndromic form of craniosynostosis characterized by the premature fusion of the metopic suture. Incidence is estimated at 1/15,000 births. Males are more frequently affected than females (sex ratio of 2:1) and the frequency of trigonocephalic twins is unexpectedly high. The premature closure of the metopic suture results in deformation of the anterior portion of the calvarium and a triangular-shaped forehead. In mild forms, only prominent ridging of the metopic suture is visible; while in more severe forms marked narrowing of the frontal and temporal regions affects the supraorbital rims leading to hypotelorism. The psychomotor development of patients is usually normal and the majority of cases are mild. Most cases are sporadic but familial forms with apparently autosomal dominant transmission have been reported (7-8%). However, the concordance rate of isolated trigonocephaly in monozygotic twins is 43%, suggesting that both genetic and environmental factors are involved in the etiology of this disorder. We report the case of a male newborn infant, having a notion of craniosynostosis in siblings (first brother) and family, the vaginal delivery was at 39 weeks of gestation, his birth weight was 3000 g, length 52 cm, and head circumference 34 cm, the Apgar score was 10/10/10, the clinical examination suspected trigonocephaly  without other birth defects, the diagnosis was confirmed by a CT scan, the brain parenchyma and the karyotype were normal . The child was followed in consultation until the age of 1 year and presented normal psychomotor development.


To evaluate the structural and molecular changes in the extracellular matrix (ECM) during the process of intervertebral disc degeneration, using animal model. th and 28th days after degenerative induction.  Wistar rats underwent intervertebral disc degeneration through 20-gauge needle puncture, and 360° rotation applied for 30 sec, representing the degenerated group, while control group was not submitted to this procedure. Histological parameters and expression of extracellular matrix molecules were evaluated in the 15 Fifteen days after the induction of intervertebral disc degeneration, significant changes were observed, such as reduction in the expression metalloprotease-9 (MMP9) and interleukins (IL-6 and IL-10). There was a significant increase in the expression of vascular endothelial growth factor (VEGF) and caspase-3. However, different alterations in the ECM were observed at 28 days, the level of collagen I, metalloprotease-2 (MMP2) and caspase-3 were enhanced. Furthermore, expression of heparanase isoforms (HPSE1 and HPSE2) mRNA were increased in the degenerative intervertebral disc. Experimental Study. The different profiles of ECM molecules observed during the intervertebral disc degeneration suggest that molecular processes such as ECM remodeling, neovascularization, apoptosis and inflammation occur.  Intervertebral disc degeneration results in the structural changes to the extracellular matrix. -,Metalloproteases (MMP) and heparanase (HPSE) are enzymes involved in degradation of the extracellular matrix molecules and play an important role in the process of intervertebral disc degeneration. -The cyokines IL-6 and IL-10 respectively, an anti-inflammatory and pro-inflammatory cytokine are also involved in disc degeneration processes. During disc degeneration neurovascular structures may be induced by the inflammatory and angiogenic factors such as the VEGF. ,Moreover, apoptotic events occurring in the nucleus pulposus cells seem to be mediated by caspases. In the present study, we evaluated the expression and distribution of structural and molecular constituents of the ECM such as collagen, metalloproteases, glycosidases (heparanase-1 and heparanase-2), cytokines, VEGF and caspase-3 in the intervertebral disc during degenerative process to elucidate alterations that may be involved with the degenerative process and to better understand the pathophysiology of the disease, contributing towards future improvements in treatment approaches as an attempt to intervene or prevent disease progression.Faculdade de Medicina do ABC, process # 003/2011. This study was approved by the Ethics in Animal Experimentation Committee of the Rattus norvergicus albinus), from the Animal House of the Faculdade de Medicina do ABC, Santo André, SP, Brazil, at 12 weeks of age , weighing between 300 and 350g. The rats were separated into three groups. Two animals were not submitted to degeneration induction and were euthanized at 28 days, representing the control group. The second group of five animals was euthanized 15 days after induction of the intervertebral disc degeneration process, and the third group of five animals was euthanized 28 days after the degeneration induction. The animals remained under the care of the animal house of the Medical School after the induction of degeneration until the time of euthanasia. For the animal model of degeneration of the intervertebral disc, 12 male Wistar rats were use  and xylazine 2% (12 mg/kg) by intraperitoneal route. The deep anesthetic plane was confirmed by the absence of corneal reflex and by the absence of reaction to deep pain provoked by the compression of the interdigits of the paws. The levels between the sixth and seventh, seventh and eighth, and eighth and ninth coccygeal vertebrae were identified by radioscopy. Induction of degeneration was performed by percutaneous puncture with a 20G needle. The needle was introduced until it reached the nucleus pulposus, turned 360°, and maintained in the same position for 30 seconds, as described in the literature. The samples were collected after 15 and 28 days after the puncture. For the euthanasia, the animals were deep anesthetized and 5 mL of arterial blood were collected from the abdominal aorta, via trans-abdominal access, causing the euthanasia by hypovolemic shock. After the euthanasia, the samples were removed and stored in RNA Holder or stored in formaldehyde (10%), respectively, gene expression and protein expression studies. (r), Dako Cytomation, Glostrup, Denmark). The sections were developed, using 3,3'-diaminobenzidine (DAB) counterstained with hematoxylin. The presence of a brown color was considered evidence of positive expression of the respective molecules. Picrosirius Red stain was done the images were analyzed with normal light and polarized light for the study of collagen fibers. Slices with 3 µm in thickness, embedded in paraffin and fixed in formalin, were deparaffinized and rehydrated. The recovery of the antigen was performed by warming of the slides at 100ºC, for 30 minutes in 10 mmol/L citrate buffer, pH 6.0. Activity of the endogenous peroxidase was blocked with an aqueous solution of 3% hydrogen peroxide for 35 minutes. The samples were incubated overnight at 4ºC with the primary antibodies: anti-MMP-2 (H-76), anti-MMP-9 (H-129), anti-interleukin-6 130326, and anti-interleukin-10 (H-160) , anti-caspase-3 (3015-100)  anti-collagen I (C 2456) , and anti-VEGF-A (18077) . Finally, the slides were incubated with a complex of streptavidin marked with peroxidase followed manufacture instructons (LSAB(r) light microscope to identify the areas that best represented the immune marking of the molecules analyzed (hot spots). In each case, quantification of the immune labelling was quantified by a digital analysis as described below. The photomicrographs with 640x480 pixels were obtained from consecutive non-coincident fields with 400X magnification using a 4300 Nikon Coolpix(r) digital camera adjusted for the same parameters. The images obtained were analyzed by the system of processing and analysis of images of ImageLab(r) (Softium Informática(r), São Paulo, Brazil), adjusted for a micrometric scale (µm), as decribed by Matos et al. The slides were analyzed with the help of a TS100 Nikon EclipseThe digital quantification was expressed by the index of expression (IE). Index of expression was obtained by the multiplication of the percentage of stained cells (PI) by the intensity of digital immune staining (ItE) for each sample, as described in the following equation and (r) reagent (Ambion by Life Technologies(tm), CA, USA), following the instructions of the manufacturer. RNA quantification was determined on the NanoVue Plus device . The reverse transcription was performed using the reverse transcriptase enzyme ImPromII(tm) , as per the manufacturer's instructions to obtain the complementary DNA (cDNA). The cDNA obtained in the reverse transcriptase reaction was used for the amplification of the isoforms of heparanase . The expression of mRNA was represented as relative value using constitutive endogenous genes, glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), thus determining the values of (-ΔCt). The expression of target-genes was analyzed using the primers for the isoforms of heparanase  and GAPDH sequences, described in the (r) SYBR Green qPCR Master Mix (2X) , following the manufacturer protocol. The reaction was submitted to a thermocycler for real-time amplification ) , with cycling of 95ºC per 10 minutes, followed by 40 cycles . Total RNA was obtained using the TrizolThe quantitative statistical analysis was performed using the GrandPad Prism 5.0 program ; to verify the occurrence of significant differences between the quantitative variables, Kruskal-Wallis's non-parametric test with Dunn's supplementary test were used in comparisons of subgroups. For the parametric analysis, the Chi-squared test was used to evaluate the qualitative variables using the SPSS program version 17.0 . In all analyses, a 5% significance level was adopted (p£0.05).Histologic and pathologic parameters evaluation are described in the Significant differences were also observed in the extracellular matrix of the intervertebral disc. Intense calcification and inflammatory infiltrate were present at 15 days after degenerative process, whilst such events represented moderate level in the samples obtained at 28 days, respectively, p = 0.022 and p = 0.025. Additionally, none of these events were detected in the control group. There were no significant differences in the analysis of fractures and fissures, myxoid and eosinophilic degeneration between the groups.  In the process of neovascularization of the disc, we observed the noteworthy presence of new vessels during the process of degeneration of the intervertebral disc and absent in the control group, despite these results are not statistically significant as shown in the In the control group we observed that the collagen fibers of the AF had a pattern of organization, with only longitudinal strands oriented along a single direction. The fibers were thickened and densely packed.  A and B AAnalysis of the expression of collagen I revealed a significant increase at 28 days relative to the degenerated group.  and 3AThe protein expression of metalloprotease MMP9 is decreased at 15 days of disc degeneration. On the other hand, a significant increase of MMP2 was noted after 28 days of intervertebral disc degeneration as demonstrated in In the analysis of the expression of VEGF, the vascular endothelial growth factor that may be involved in the neovascularization, we noted a significant increase 15 days after the disc degeneration relative to the controls.   Digital The values obtained by the index of expression (IE) of caspase-3, a protease directly involved with mechanisms of cellular apoptosis, increased significantly during the degenerative process of the intervertebral disc at 28 days compared to the control group.  and 7 The expression of the messenger RNA (mRNA) of the isoforms of heparanase was carried out by quantitative RT-PCR analysis, which demonstrated that the degenerated intervertebral discs presented a significant reduction in the expression of HPSE1 and HPSE2 after the induction of the degenerative process when compared to the control group, as is shown in In the histopathologic evaluation of the degenerative intervertebral samples of rats we noted evident cellular alterations such as apoptosis that increased gradually during the development of the degenerative process (14 and 28 days of induction of degeneration), mild regeneration, intense calcification and moderate presence of inflammatory infiltrate. The study done by Haschtmann and coworkers demonstrated that in the degenerative intervertebral disc of the rat model, the proportion of cells in apoptosis also increased significantly, corroborating our results. The degeneration of the intervertebral disc altered significantly the structural organization of the collagen, since degenerative samples presented disordered fibers that are not as thick as control samples representing new collagen fibers, beyond to increase type I collagen expression. It is known that MMP2 has more expression in degenerative processes and that it participates directly in remodeling of the collagen by regulating the activity of the gelatinases. ,It is acknowledged that metalloproteases are involved with extracellular matrix remodeling. , Inflammatory cytokines have a fundamental role in the phases of degeneration of the intervertebral disc. The start of the disease is characterized by an initial lesion where the cells regulate the expression of inflammatory cytokines such as TNF, IL - 1β, and IL-6, as well as degradation molecules of the extracellular matrix, resulting in tears, fissures causing mechanical instability to the disc. In the second phase of the disease, the cytokines are released activating the infiltration of leukocytes into the tissue and the inflammatory response is accompanied by neovascularization and the appearance of nervous fibers. The final phase is characterized by sensitization of the nervous endings mediated by the inflammatory process and neurotrophins resulting in pain.  In our study, we obtained a significant increase in the protein expression of IL-6 an anti-inflammatory cytokine, while there was a significant decrease of IL-10 that is a pro-inflammatory cytokine at the same time (15 days) of disc degeneration. The histologic evaluation of the tissues showed a moderate level of inflammatory process, which may suggest a balance between the action of such interleukins. Moreover, the abnormal production of pro-inflammatory molecules in the degenerative process of the disc can trigger a series of pathogenic responses in the cells of the intervertebral disc promoting autophagy, senescence, and cellular apoptosis. VEGF expression are enhanced at 15 days after the intervertebral disc degeneration and neovascularization was also present in the degenerative samples and absent in the control samples (non affected by disc degeneration). Furthermore, taken together these results are consistent with those of literature. Caspase-3 represents a marker of apoptosis induction and its expression increases gradually during the degenerative process of intervertebral disc High level of HPSE1 obtained in the samples submitted to intervertebral disc degeneration indicates that this enzyme is possibly involved with the processes of tissue remodeling during degenerative process. Our data confirm that the isoform HPSE2 are also possibly involved in the development of intervertebral disc degeneration, due to increased expression compared to the non-degenerative discs.The alteration of metalloproteases, collagen, glycosidases, VEGF, caspase-3, and interleukins observed in the present study, suggest an intense remodeling process of the extracellular matrix of the degenerative intervertebral discs.Better understanding of the molecular mechanisms involved in the intervertebral disc degeneration is important to elucidate the pathophysiology of the degenerative disc disease that affects the population worldwide and directly impacts the quality of life of the individuals.


The number needed to treat (NNT) is a simple measure of a treatment’s impact, increasingly reported in randomized trials and observational studies, but often incorrectly calculated in studies involving varying follow-up times. We discuss the NNT in these contexts and illustrate the concept using several published studies. While the computation of the NNT is founded on the cumulative incidence of the outcome, several published studies use simple proportions that do not account for varying follow-up times, or use incidence rates per person-time. We show how these approaches can lead to erroneous values of the NNT and misleading interpretations. For example, a trial of 3,845 very elderly hypertensives randomized to a diuretic or placebo reported a NNT of 94 treated for 2 years to prevent one stroke, though the correct approach results in a NNT of 63. Also, meta-analyses involving trials of differing lengths often report a single NNT, such as the meta-analysis of 22 trials of the anticholinergic tiotropium in chronic obstructive pulmonary disease that reported a NNT of 16 patients “over one year,” even if the trials varied in duration from 3 to 48 months, with the actual NNTs varying widely from 15 to 250. Finally, we describe the value of the NNT in assessing benefit–risk, such as low-dose aspirin use in secondary prevention of mortality assessed against the risk of gastrointestinal bleeding. As the “number needed to treat” becomes increasingly used in the comparative effectiveness and safety of therapies, its accurate estimation and interpretation become crucial to avoid distorting clinical, economic, and public health decisions. The number needed to treat (NNT) is a simple and user-friendly measure of the impact of a treatment on a given disease outcome, introduced over 25 years ago and now used extensively in randomized trials and observational studies.The simplicity of this measure, both in terms of calculation and interpretation, has led to its increasing use in clinical research and prominent presence in publications. However, its incorrect computation, despite or perhaps because of its simplicity, has led to inappropriate and misleading conclusions.In this paper, we review the “number needed to treat” measure and present some examples of its misuse, generally related to the inappropriate consideration of time. We also describe the proper calculation techniques and its accurate interpretation.The NNT is based on the frequency of disease outcome measured as a cumulative incidence of the outcome per number of patients followed over a given time period. This will result in a proportion of patients with the outcome, which we mechanically tend to write as a percentage, such as 0.5/100, 2/100, or 5/100, to make frequencies easily comparable. Instead of using percentages to facilitate comparisons, we could alternatively express the proportions by fixing the numerator at 1. In our example these become 1/200, 1/50 and 1/20, which when inverted to 200:1, 50:1, and 20:1 represent the number of patients that need to be observed to find one patient with the outcome. This reversed representation of the proportion forms the basis for the NNT.The NNT relates to the effectiveness of a treatment, usually based on a randomized or observational trial comparing two treatment alternatives, measured by the treatment difference in the proportion of patients with the adverse disease outcome over a fixed follow-up time-period. This difference will represent the proportion of patients for whom the adverse outcome was prevented due to treatment. Inverting this difference will produce the number of patients that need to be treated to prevent one patient with the outcome.1For example, consider a trial of the effectiveness of adding a new inhaler to the usual maintenance treatment of chronic obstructive pulmonary disease (COPD) compared with placebo, where 15% of patients on placebo had a fatal exacerbation compared with 10% with the new inhaler during the 1-year follow-up. Thus 15%–10%=5% represents a prevented mortality of 5/100, that is five patients are prevented from a fatal exacerbation for every 100 patients who added the new inhaler over 1 year instead of adding placebo. The NNT is then simply 1/(15%–10%)=100/5=20. This inversion suggests that rather than using the 5/100 measure of prevented mortality, the NNT value of 20 will provide the more vivid interpretation of one patient avoiding the fatal outcome for every 20 patients treated for 1 year.A reality of most randomized trials or observational studies is that the follow-up is not equal for all patients but varies, so that the calculation of the proportion with the outcome by the end of the follow-up will require consideration of this variation in follow-up times. In this case, the Kaplan–Meier approach must be used to estimate the correct proportions with the outcome over time; it accounts for varying follow-up times and provides a curve for the cumulative incidence over time.12The long-acting anticholinergic tiotropium and the fluticasone-salmeterol combination are two popular treatments in COPD. A meta-analysis of 22 tiotropium randomized trials involving over 23,000 COPD patients reported, in comparison with placebo, a NNT of “16 patients over one year with tiotropium to prevent one exacerbation.”15A randomized trial of the effect of adding zoledronic acid to endocrine therapy in premenopausal women with endocrine-responsive early breast cancer involved 1,803 patients who were followed for up to 84 months.n=743) or placebo (n=741) for 240 days.A randomized trial of treatment for herpes simplex virus HSV type 2 (HSV-2) was conducted where 1,484 subjects were randomly assigned to the nucleoside analogue valacyclovir  serious form of iron overload syndrome (IOS), which results in liver failure in almost 50% of patients within a year of diagnosis. A total of 3,000 patients were studied in this hypothetical three-arm trial, with 1,000 randomized to a treatment called Fedom, 1,000 randomized to another treatment called Feclad, both compared with 1,000 patients given placebo, and all patients followed for 1 year or until liver failure.While the trial was intended to follow all patients for 1 year, 60% were censored before that time. Thus, the mean follow-up was 7 months, during which there were 324 liver failures in the placebo group, compared with 230 and 238 in the Fedom and Feclad groups, respectively. Several trials have used the simple proportion of patients with the outcome to compute the NNT. Only if all patients are followed for the full study period does the simple proportion equal the cumulative incidence of the outcome at 1 year as computed by the Kaplan–Meier approach. However, when the follow-up times vary, as is generally the case with most trials, the simple proportion is not a valid estimate of the cumulative incidence and can thus lead to erroneous and misleading values of the NNT.Note that the importance of the Kaplan–Meier approach is not as crucial in studies where the follow-up is short and mostly complete, in which case the simple proportions and Kaplan–Meier cumulative incidence are practically equal.22In the trial of nucleoside analogues against herpes simplex virus type 2 (HSV-2), the NNT calculation of 38 persons with recurrent genital herpes treated with valacyclovir for 1 year to prevent one case of HSV-2 infection was also based on the simple proportion of patients with HSV-2 infection.Another measure that has been used to quantify the incidence of the outcome in calculating the NNT has been the incidence rate as a way to account for varying follow-up times. The incidence rate is computed as the number of patients with the outcome divided by the total amount of person-time generated by the follow-up of the study patients. Using this, some authors have computed the NNT as the inverse of the difference between the incidence rates for the two groups under study. However, here again, this can lead to incorrect values of the NNT.Several studies have improperly used the incidence rate approach in computing the NNT.Similarly, in the Collaborative Atorvastatin Diabetes Study (CARDS), the authors used incidence rates to report that “27 patients would need to be treated for 4 years to prevent one (major cardiovascular) event.”27Lastly, the previously mentioned trial of 3,845 very elderly hypertensives randomized to a diuretic or placebo also used incidence rates to compute the NNT of 94 treated for 2 years to prevent one stroke.The meta-analysis of the 22 trials of the anticholinergic tiotropium that involved over 23,000 COPD patients reported a NNT of 16 patients “over one year” with tiotropium to prevent one exacerbation.To evaluate the NNT for 1 year of treatment, the meta-analysis could have restricted its analysis exclusively to the 1-year trials. Indeed, for the six 1-year studies, the proportion of patients with a COPD exacerbation is 37.4% of patients on tiotropium compared with 44.2% on placebo, leading to a NNT over 1 year of 15, which coincidentally is practically equal to the reported NNT of 16 based on all 22 trials of variable duration. Note, however, that NNT is 72 for the 3-month trials and 250 for the 48-month trials.15Lastly, it is important to note that even for the 1-year trials, the follow-up times likely varied between patients, so that the simple proportions used can be inaccurate to compute the NNT, as shown in The NNT can also be useful in evaluating the balance between a risk and benefit of a drug. Indeed, the number of patients that need to be treated to prevent an outcome of the disease can be compared to the number needed to treat to induce a patient having a harmful side-effect. For example, the NNT was useful in weighting the benefit of inhaled corticosteroids in preventing COPD exacerbations against their risk of inducing pneumonia.Another example is the previously mentioned meta-analysis of low-dose aspirin use, where prevention of mortality was assessed against causing gastrointestinal bleeding.In contrast, an analysis pooling data from four trials to assess the benefit–risk of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty properly used the Kaplan–Meier curves to compute the NNTs.The number needed to treat is a simple and appealing measure of the impact of a treatment that has been, since its publication over 25 years ago, increasingly used in the reporting of study results. It provides the number of patients that need to be treated to prevent the disease outcome in one patient, over a given time period. However, despite and perhaps because of its simplicity, the NNT is often miscalculated. Generally, the incorrect computations arise from the inappropriate consideration of time.Indeed, trials generally result in varying follow-up times so that the calculation of the NNT inherently requires that the cumulative incidence of the outcome be used in its computation. We note, however, that many studies either use simple proportions or incidence rate per patient-time, rather than Kaplan–Meier curves, thus not properly accounting for varying follow-up times. In our hypothetical trial with varying follow-up times, we noted that using the incorrect simple proportion changed the NNT of a treatment from 77 to 12, or from 6 to 11. As well, using the incorrect incidence rate changed the NNT of a treatment from 77 to 5.Another issue is the tendency of some studies to extrapolate the NNT time horizon beyond the study time-period. For example, the trial evaluating a hip protector to prevent hip fractures was a 2-year study.These miscalculations and misinterpretations of the NNT are, alas, still very current, even after 25 years of existence.34P value or a confidence interval to the NNT, so that the role of chance and the size of the study are reflected in the calculation. Computing the NNT for a non-significant treatment effect will result in an apparent anomaly in the confidence interval—it will include negative values for the NNT, which will reflect a range of NNT values where the study treatment is inferior to the comparison treatment.37Some issues were not discussed in this paper, such as the role of random error in the calculation of the NNT. It is of course important to attach a In all, as the “number needed to treat” becomes increasingly used to evaluate treatments, proper calculations are crucial to avoid distorting health care economic calculations and public health evaluations. The appropriate use of the cumulative incidence function over time will avoid important biases and provide accurate estimates of this appealing measure of treatment impact.