The study aimed to evaluate the correlations between the clinical and paraclinical data in the lateral bulbar infarction, benefiting from the access to the semiologic characteristics of a group studied and the MRI angiography, without a contrast agent, through the 3D TOF technique combined with MIP, as an imaging technique for the evaluation of the arterial lesion. The study group included 20 patients with lateral bulbar infarction, 14 men, and 6 women aged between 21 and 80 years, the mean age being 56, 9 years, who were enrolled in the study in the period 2012 and 2014, following the admission in the National Institute of Neurology and Neurovascular Diseases. All the patients enrolled in this stage study, performed brain MRI - in the Medinst laboratory, which included the following sequences T1, T2, Flair, DWI, MRI angiography without contrast agent (3D TOF combined with MIP). The study was retrospective. Following the analysis of the 3D TOF sequences combined with MIP, it was found that in the group studied, 8 patients had damage at the level of the vertebral artery, 2 at the level of the posterior inferior cerebellar artery and 10 patients presented mixed lesions of both the vertebral artery and of the PICA artery. In terms of the mechanism involved, most of the lateral bulbar infarctions were generated by arterial dissection (9 cases) and 6 cases had atheroma as etiology. Regarding the risk factors, dyslipidemia and smoking predominated in the studied group and the most common signs and symptoms were gait abnormalities, the ataxia of the limbs, dysphonia, and Horner syndrome.Abbreviations: 3D TOF = 3D time of flight angiography, MIP = maximum intensity projection, MRI = magnetic resonance imaging, CT = computed tomography, FLAIR = fluid attenuated inversion recovery, DWI = diffusion weighted imaging, HTA = hypertension, DZ II = diabetes mellitus, VA = vertebral artery, PICA = posterior inferior cerebellar artery, VG = vertigo, NT = nystagmus, N/ E = nausea/ emesis, DP = dysphagia, PVP = pharyngeal/ vocal cord paresis, HS = Horner syndrome, PTH = pain/ temperature hypesthesia, LA = ipsilateral limb ataxia, GA = Gait ataxia, C-R-F = Cardiovascular risk factors, L = left, R = right The diagnosis of this syndrome often depends on the clinical symptoms and signs. The nuclear magnetic resonance has become the preferred imaging method in studying the lateral bulbar infarction due to the spatial resolution and the increased contrast between the normal and pathological tissues [2]. Some of the vascular causes responsible for the lateral bulbar infarction are the damage of the vertebral artery or of the posterior inferior cerebellar artery by dissection, thromboembolism, or atherosclerosis. The angiography with a digital subtraction is the gold standard for the diagnosis of the arterial lesions at the level of the vertebral artery, and of the posterior inferior cerebellar artery with a CT angiography and MRI angiography. However, the angiography with a digital subtraction is an unsuitable investigation for the screening of the arterial lesions due to the invasiveness and risk of an iatrogenic vascular accident [3]. The advanced MRI techniques are available for the detection and assessment of the atherosclerotic plaques and of the vascular wall at the level of the intracranial arteries . The study aimed to evaluate the correlations between the clinical and paraclinical data in the lateral bulbar infarction, having as a technique for the assessment/ description of the arterial lesion, mainly the MRI angiography, without contrast agent, through the 3D TOF technique combined with MPI.The lateral bulbar infarction is easily recognizable due to the appropriate signs and symptoms, which fall within the Wallenberg syndrome. It is responsible for about 2% of all the strokes . The arterial dissection is thus defined in the 3D TOF sequence as true and false double lumen at the lesion place, the atheroma is defined as the thickening of the wall between the lumen and the vessel wall, and the thromboembolism is defined as a damage of the arterial wall that is not fulfilling either the criteria of dissection or of atheroma . Correlations between the typical clinical manifestations that occur in the lateral bulbar infarction and the anatomical structures involved are presented in Thus, the pain, the numbness and the objective sensitivity disorder at the level of the ipsilateral hemiface are given by the damage of the descending tract and of the V nerve nucleus, the vertigo, nausea, vomiting, nystagmus and diplopia occurring while affecting the vestibular nuclei, the ipsilateral Horner syndrome, by damaging the descending sympathetic tract; dysphagia, dysphonia, the ipsilateral vocal cord paresis by affecting the IX and X nerve fibers, the ataxia of the ipsilateral limbs, the fall in the side of the lesion, and the sensation of lateropulsion occur through the damage of the restiform body, of the olivocerebellar fibers, of the cerebellar hemispheres, and of the spinocerebellar tract. Paraesthesia at the level of the ipsilateral arm, torso, and leg may also occur in the Wallenberg syndrome by affecting the cuneate and gracilis nucleus and the spinothalamic tract. A damage of the contralateral thermoalgic sensitivity of the torso and limbs and, more rarely, ipsilateral, may also occur.Fig. 1).Regarding the risk factors of the patients included in the study, 7 patients had HTA, 2 patients had diabetes mellitus, 6 were smokers, 10 had hyperlipidemia, 1 patient presented cardiovascular risk factors and 7 patients did not present risk factors . 8 lateral bulbar lesions were on the left and 12 on the right Table 3).In the study group, out of the 20 patients included in the study, 8 presented lesions located strictly at the level of the vertebral artery, 10 had mixed damage of VA and PICA, two patients presented PICA damage, without lesions at the level of the vertebral artery (Table 4).According to the criteria above, after analyzing the imaging investigations (the examination of the 3D TOF sequences combined with MIP), a classification of the type of lesion present at the level of the vertebral artery  was presented: out of the 20 patients included in the study, 9 patients presented an arterial dissection - according to the criteria mentioned above, 6 had the atheroma as vascular etiology, and one patient did not meet either the criterion of dissection or of atheroma (thromboembolism) (Table 5).A further study of the characteristics of the group of patients included in the study from the group of patients with PICA plus damage , 8 of them were men out of whom: 3 presented vertigo, 3 nystagmus, 5 nausea/ emesis, 4 dysphagia, 4 vocal cord paresis, 1 Horner syndrome, 5 pain/ temperature hypesthesia, 5 ipsilateral limb ataxia and 7 gait ataxia. In the other group, which involved only the vertebral artery, 5 patients were men, 4 presented vertigo, 3 had nystagmus, 3 had nausea/ emesis, 4 presented dysphagia, 7 presented pharyngeal/ vocal cord paresis, 8 had Horner syndrome, 8 had pain/ temperature hypesthesia, 8 had ipsilateral limb ataxia, 8 had gait ataxia , 50 had an involvement of both arteries (10 out of 20) and 10% had a PICA involvement (2 cases out of 20). Regarding the neurological signs and symptoms, the results obtained in the patients studied were compared to those obtained by Jong S Kim, who performed one of the most extensive studies in the patients with lateral bulbar infarction (130 patients). In Kim’s study, the most frequent symptoms were the sensory disorders (96%) compared to the current study in which sensory disorders were obtained at a rate of 75%. Regarding the other signs and symptoms, Kim obtained the following results: gait ataxia 92%, Horner sign 88%, pharyngeal/ vocal cord paresis 88%, dysphagia 84%, vertigo 57%, nystagmus 56%, limb ataxia 55%, nausea/ emesis 52%. In the current study, gait ataxia was found in 90% of the patients, Horner sign in 60%, pharyngeal/ vocal cord paresis in 70%, dysphagia in 60%, vertigo in 45%, nystagmus in 45%, limb ataxia in 80%, nausea/ emesis in 35% [10]. The similar results between the two studies were obtained regarding the gait ataxia, the other symptoms and signs significantly differing in percentage (the above-mentioned data).According to the studies conducted by Fisher et al. regarding the lateral bulbar infarction, 14, 3% of the patients had PICA involvement, 38, 1% vertebral artery involvement (VA) and 26, 2% involvement of both arteries [There were several limitations of the study. The small number of cases prevented the obtaining of certain generalizations. However, it should be mentioned that the lateral bulbar infarction is a quite rare pathology and that is why even the studies on small groups of patients are significant. Technical limitations: not all the hospitalized patients performed high-resolution contrast-enhanced three-dimensional imaging with spoiled gradient-recalled sequence (HR-CE 3D-SPGR) as it was initially desired and that is why only the patients who performed the 3D TOF common sequence with MIP were included in the study. AcknowledgmentsThanks and respect to Academician Professor Popa Constantin, MD, for the permanent and constant guidance. Without his involvement, this article would not have been possible. DisclosuresNone


The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by physically interacting with the receptor, and/or indirectly, by altering the bulk properties of the membrane. While the exact role of oligomerization in the function of class A GPCRs such as the μ-opioid receptor (MOR) is still unclear, insight as to how these receptors oligomerize and the relevance of the lipid environment to this phenomenon is crucial to our understanding of receptor function. To examine the effect of lipids and different MOR conformations on receptor oligomerization we carried out extensive coarse-grained molecular dynamics simulations of crystal structures of inactive and/or activated MOR embedded in an idealized mammalian plasma membrane composed of 63 lipid types asymmetrically distributed across the two leaflets. The results of these simulations point, for the first time, to specific direct and indirect effects of the lipids, as well as the receptor conformation, on the spatio-temporal organization of MOR in the plasma membrane. While sphingomyelin-rich, high-order lipid regions near certain transmembrane (TM) helices of MOR induce an effective long-range attractive force on individual protomers, both long-range lipid order and interface formation are found to be conformation dependent, with a larger number of different interfaces formed by inactive MOR compared to active MOR. The μ-opioid receptor (MOR) is an important pharmaceutical target in the treatment of pain. In order to develop novel pain therapies, devoid of the serious side-effects of present opioid analgesics, we need to understand the fundamentals of how MOR works on the molecular level. While some studies suggest that oligomers of MOR could play a role in signaling, how MOR forms dimers, which interfaces form, and the exact role of oligomers in MOR function remain unclear. While research has shown that the membrane environment can affect membrane protein function, most previous computational work to study oligomerization has been performed in a very simple membrane. Here, we use molecular dynamics simulations of MOR in a heterogeneous plasma membrane model (comprising 63 lipid types) to investigate how the presence of the protein modulates its lipid environment, affecting species distribution and sculpting characteristic order and thickness profiles around the receptors. Such modulations, in turn, induce long-range interactions between the proteins and favor the formation of specific dimeric conformations. The position lipid molecules relative to the protomers was described as dvd+nnd in the frame of reference given by the versor vd∝R1–R2 and its normal nd. We report averages of membrane thickness and order over Ωα, Ωβ, and n<r0 (where r0 = 1.7 nm is the average protomer radius), as a function of r (protomer distance) and d (lipid position). Only frames for which no other protein was found within r0 from the line connecting the COMs  of the two protomers were included in the analysis. The averages are calculated and reported for d∈.The analysis of the lipids around receptor protomers was performed on the final 2 μs of the membrane equilibration part of the simulation–in which the proteins were kept fixed with position restraints–and on the protomers extracted from the production runs. In the latter, a receptor was considered monomeric if the distance between the center of mass of the protein and every other protein was at least 5 nm. Since the atomic coordinates were recorded every ns and each frame has 16 receptors, each lipid distribution around the receptors was calculated from 5×2000×16 sets of lipid-protein positions. The analysis of the lipids around the dimers was performed on the frames from the final 1 μs of simulation time of the high receptor density production runs, which was also used for interface clustering. The ROH beads of the CHOL or the first linker bead (GL1 or AM1) of the non-sterol lipids were used for the lipid analysis  of each helix was calculated in order to obtain a distribution of residence times per lipid species and helix per run. The total mean residence times and standard deviation were obtained by averaging over the distributions from each replica.2 = Tr(DTD) of the difference of contacts maps D as a dissimilarity measure. An interface was considered to be formed when at least ten residues on each protomer formed contacts with the other protomer, with a contact defined as two backbone beads lying within 0.8 nm of each other. Helices with three or more residues forming contacts were used in the interface name. The relative frequency of each observed interface and their variance were estimated using a multinomial model Xj ~ Multinomial, where Xj is the number of observed dimers for interface j and n is the total number of observed dimers. Specifically, the well-known relation to the Poisson model was exploited to rewrite the model as Xj ~ Poisson(λj) and pj = λj/∑ λj. We took a Bayesian approach, and sampled the posterior distributions of pj with normal uninformative (standard deviation 100) priors on γj = log(λj) using the observed values of Xj for each trajectory. Results are reported as mean and 95% credible intervals. Sampling was performed with the rstan 2.8.0 interface to the Stan language [All interface analysis was performed on the high-density simulations. To characterize the interfaces formed during the production runs, k-means clustering was performed on the final 1 μs of the trajectories, using the Euclidean norm dlanguage . The RMSlanguage .S1 TableAll residues listed are in contact with either the inactive or active receptor at least 10% of the simulation time. Residues exhibiting the greatest difference between the two receptor conformations are shown in bold.(PDF)Click here for additional data file.S2 TableThe mean fraction of dimers belonging to each specific interface is reported along with its 97.5% credible intervals. The most frequently observed interfaces for each dimer type are highlighted in bold.(PDF)Click here for additional data file.S3 TableResidues in contact with CHOL for more than 75% of the simulation time are in bold.(PDF)Click here for additional data file.S1 FigStructure of A) a cholesterol, B) a PC/SM lipid, and C) a GM lipid with the ROH, GL1, and AM1 beads used in the lipid analysis colored in cyan. The headgroup beads are in pink and the remaining tail beads in grey.(PDF)Click here for additional data file.S2 Fig1-3, D) PS, and E) GM around individual protomers during the final 2 μs of the low receptor density simulations with the BB beads of the receptors fixed. The dots indicate the centers of mass of the BB beads of the receptor helices.Lipid distributions of A) PA, B) PI, C) PIP(PDF)Click here for additional data file.S3 Fig1-3 (1.6%), CER (0.1%), and DAG (0.5%). The total number of lipids in the upper and lower leaflets was approximately 805 and 750, respectively for the high receptor density membrane and 3200 and 3000 for the low receptor density membrane.‘Other’ in the upper leaflet includes: CER (0.7%), LPC (1.0%), and DAG (0.4%). ‘Other’ in the lower leaflet includes: PA (1.5%), PIP(PDF)Click here for additional data file.S4 FigThe data is averaged over all lipids, excluding the ones that flip-flop across the membrane . For the order, a value of 0 (orange color) indicates a fully ordered lipid tail, and the larger the value, the more disordered the tail. The units of thickness are nm. In both cases, the white color is set to the average value of the simulations with the inactive receptors. The center of mass of the seven TM helices are indicated by the colored dots as follows: TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively.(PDF)Click here for additional data file.S5 FigThe data is averaged over all lipids, excluding the ones that flip-flop across the membrane . For the order, a value of 0 indicates a fully ordered lipid tail, and the larger the value, the more disordered the tail. The units of thickness are nm. In both cases, the white color in the color bar is set to the average value of the simulations with the inactive receptors. The centers of mass of the seven TM helices are indicated by the colored dots as follows: TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively. The ‘I’ and ‘A’ indicate if the receptor is in the inactive conformation or the active conformation.(PDF)Click here for additional data file.S6 FigFor each bin, the average order is plotted vs. the average thickness.(PDF)Click here for additional data file.S7 FigFor the thickness, the average and standard error are indicated by a black line and a grey band, respectively. The overall average value of the order is indicated by red dashed lines in the bottom panels. The location of the center of mass of the helices is indicated by the vertical lines and TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively. Because of the large tilt of TM3, its center of mass appears to the right of TM4.(PDF)Click here for additional data file.S8 FigFor the thickness, the average and standard error are indicated by a black line and a grey band, respectively. The overall average value of the order is indicated by a red dashed lines in the bottom panels. The location of the center of mass of the helices is indicated by the vertical lines and TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively. Because of the large tilt of TM3, its center of mass appears to the right of TM4.(PDF)Click here for additional data file.S9 FigThe angle θ  is the angle between the protein principal axis and the normal to the membrane, while φ  is the angle between the projection of the principal axis on the xy plane and the projection of the vector connecting the center of mass of the protein with the center of mass of helix TM1.(PDF)Click here for additional data file.S10 FigThe thick lines are the average of the five individual runs which are shown as thin lines. The individual runs are an average over all 16 protomers in the protein array.(PDF)Click here for additional data file.S11 FigThe data is averaged over all lipids, excluding the ones that flip-flop across the membrane . A value of 0 (orange color) indicates a fully ordered lipid tail, and the larger the value, the more disordered the tail. In both cases, the white color of the color bar is set to the average value of the simulations with the inactive receptors. The centers of mass of the seven TM helices are indicated by the colored dots as follows: TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively.(PDF)Click here for additional data file.S12 Figr and the lipid position d for the following interfaces: TM5/TM5 and TM1,2,H8/TM1,2,H8 for the active MOR , and TM1,2,H8/TM5 for the inactive or active MOR . Trajectories from both the high and low receptor density simulations with the receptors free to move were used to generate the plots.Average lipid thickness (upper triangle) and order (lower triangle) calculated as a function of the protein-protein distance (PDF)Click here for additional data file.S13 Fig(PDF)Click here for additional data file.S14 FigThe error bars represent the deviation over the five runs.(PDF)Click here for additional data file.S15 Fig(PDF)Click here for additional data file.S16 FigThe data in the plots for the membranes with receptors are from the final 2 μs membrane equilibration in the simulations with high receptor density and the BB beads of the receptors fixed.(PDF)Click here for additional data file.S17 FigKinetic network of the cholesterol movement in the z-direction as a function of the distance from the protein for the A) inactive and B) active MORs generated with the plot_network routine of pyemma using the final 2 μs of membrane equilibration of the simulations with high receptor density and the BB beads of the receptors fixed. The initial geometric clustering was performed using the contacts formed between a single cholesterol molecule and the residues of the protein. The five pathways with the highest fluxes are shown with the thickness of the arrows indicative of the relative flux. The size of the circle is proportional to the size of the state. The states are colored according to their average order with orange corresponding to a cholesterol oriented parallel to the membrane normal and dark purple representing a perpendicular orientation.(PDF)Click here for additional data file.S18 FigValues for the simulations with inactive or active receptors are reported in blue and red, respectively.(PDF)Click here for additional data file.S19 FigModel structures of the A) inactive/inactive MORs interacting at the TM1,2,H8/TM4 interface and B) active/active MORs interacting at the TM1,2,H8/TM1,2,H8 interface during the final μs of the high density simulations in which the BB beads of the receptors were kept fixed. Helices involved in the interface are colored by frequency of interaction with cholesterol (white to blue to green indicates low to high probability).(PDF)Click here for additional data file.S20 FigSnapshot of the production runs of the simulations with high receptor density at 0, 5, 10, and 20 μs for the A) inactive, B) active, and C) mixed arrays of MOR. The lipids are in grey, the inactive proteins in blue, and the active proteins are red.(PDF)Click here for additional data file.S1 MovieThe snapshots in (MP4)Click here for additional data file.


Huntington’s disease (HD) is a neurodegenerative disorder that affects 5 to 10 people per 100,000 inhabitants and it is caused by an aberrant expansion of trinucleotide CAG repeats (>36) in the exon 1 of the huntingtin gene. As a consequence of this mutation, a complex symptomatology of cognitive decline, motor impairment, personality changes and other alterations is usually manifested in mid adulthood until the final death of the patient. Despite the establishment of the monogenic causative nature of HD twenty years ago, there is still no effective therapy.In the early 2000s a promising ameliorative strategy was conceived after the observation of deficiencies in histone acetylation levels in several HD models, and the detection of an enzyme involved in this modification, the acetyltransferase CREB-binding protein (CBP), in mutant huntingtin aggregates . BecauseIn 2013 we published the most complete genomic landscape of histone acetylation in the context of mutant huntingtin expression, namely the ChIP-seq analysis of acetylated lysines 9 and 14 of histone H3 and acetylated lysine 12 of histone H4 in the hippocampus of the transgenic N171-82Q strain . This woFos), brain area  or stage of the disease . In fact, whereas only 12% of the hypoacetylated genes in the hipocampus of N171-82Q was also transcriptionally altered in this brain area and animal model, this percentage was increased to 41% when also considering the genes transcriptionally altered in other datasets generated from diverse HD scenarios  [In this follow-up study  we also


At present, sustainability is of major importance in the cement industry, and the use of additions such as silica fume as clinker replacement contributes towards that goal. Special foundations, and particularly micropiles, are one of the most suitable areas for the use of sustainable cements. The aim of this research is to analyse the effects in the very long-term (for 600 days) produced by sulphate attack in the microstructure of grouts for micropiles in which OPC (ordinary Portland cement) has been replaced by 5% and 10% silica fume. This line of study is building on a previous work, where these effects were studied in slag and fly ash grouts. Grouts made using a commercial sulphate-resisting Portland cement were also studied. The non-destructive impedance spectroscopy technique, mercury intrusion porosimetry, and Wenner resistivity testing were used. Mass variation and the compressive strength have also been analysed. Apparently, impedance spectroscopy is the most suitable technique for studying sulphate attack development. According to the results obtained, grouts for micropiles with a content of silica fume up to 10% and exposed to an aggressive sulphate medium, have a similar or even better behaviour in the very long-term, compared to grouts prepared using sulphate-resisting Portland cement. Moreover, the majority of these additions are residues from other industrial processes, and their reuse is also a benefit. On the other hand, some of them are active additions, which means that they can react with water or with Portlandite that has been produced as a product of hydration reactions of clinker. This reaction forms new hydrated products that boost the cement-based materials’ properties [Recently, the use of additions as clinker replacement in cement manufacturing has become very common ,2,3,4,5.operties ,7,8,9,10In relation to silica fume, research indicates that this addition improves the microstructure and properties of cement-based materials ,12,13,14The micropiles’ standards ,16,17 doRegarding the durability of micropiles, it is important to insist that the reinforcement elements of this special geotechnical work are embedded in cement grouts instead of concrete, as in most of civil engineering and building structures. Then, these elements could differently be affected by the attack of aggressive substances, especially if sustainable cement with an active addition, such as silica fume, is used.A very common aggressive substance present in soils and groundwater is the sulphate ion; therefore, the micropiles can be exposed to their attack. The attack produced by sulphate ions is complex . In the 2SO4 could play as an activator of pozzolanic reactions of silica fume, which would more quickly reduce the Portlandite existing in the cementitious system.On that subject, the positive effect of silica fume on sulphate attack resistance is relatively well known ,23. It hWith respect to sustainable grouts for micropiles exposed to sulphate attack, recent research  has obseOn the other hand, it is interesting to note another recent work in relation to the study of the microstructure of cement-based materials that incorporate silica fume exposed to sulphate attack using the novel non-destructive impedance spectroscopy technique . In thatThe present research continues both abovementioned works ,26, but Three types of cement grouts were studied in this research. The first one was prepared using a commercial sulphate-resisting Portland cement, CEM I 42.5 R/SR   aqueous solution by weight. In order to monitor the changes in the microstructure and the mechanical strength of the grouts in the long-term from the sulphate attack, the exposure period was extended up to 600 days. The sodium sulphate solution was replaced every 60 days during the studied period. The volume of sulphate solution was approximately four times the volume of the samples, as recommended by the ASTM C 1012-04 standard [Once the curing period finished, the specimens were exposed to an aggressive sulphate medium. This medium was 15% reagent grade anhydrous sodium sulphate , made of flexible graphite, and attached to a copper piece with the same diameter. Both contacting and non-contacting methods were used [1 is associated only with the percolating pores of the sample, while the resistance R2 provides information about all its pores. On the other hand, the capacitance C1 is related to the solid fraction of the sample, and the capacitance C2 is associated to the pore surface in contact with the electrolyte, which fills the pore network of the material.The impedance analyser used for performing the measurements on cement grouts was an Agilent 4294A , which allows capacitance measurements in the range from 10ere used ,35. The ere used  . The samples were dried in an oven for 48 h at 50 °C prior to the test. They were obtained from discs of 2 cm-height. For each age, two measurements were performed on each grout type. Total porosity, pore size distribution and the percentage of mercury (Hg) retained at the end of the experiment were studied. The testing ages were 28, 60, 90, 120, 180, 365, and 600 days.The monitoring of samples’ mass changes is frequently used for studying the behaviour of cementitious materials exposed to sulphate attack ,41. HereThe compressive strength is a commonly used parameter for following the attack produced by sulphates in cement-based materials ,42,43. F1 are depicted in 1 values were observed for silica fume grouts during the entire exposure period, which reached their maximums between 200–250 hardening days, depending on the content of addition. Moreover, the R1 increasing rate was also greater for those grouts compared to CEM I SR ones. Since the abovementioned ages, the resistance R1 of silica fume grouts showed a slight decrease until 600 days, which was more noticeable for those with 10% silica fume (SF10). For CEM I SR, the R1 increase was slower, with a maximum at approximately 400 days, and scarcely falling for up to 600 days.The results of resistance R2, results can be observed in 1, although the difference between grout types is more marked. The grouts with 10% silica fume (SF10) had the greatest R2 values throughout the studied time. For that type of grout, the fastest rise of this parameter was observed until 150 days; which then slowed down between exposure days 150–600. The R2 evolution for 5% silica fume (SF5) grouts was very similar to that described for SF10 grouts, although the R2 values of the SF5 group were lower. The smallest R2 corresponded to CEM I SR grouts, in which this parameter hardly changed with time.In relation to resistance R1 results are represented in 1 value was different, depending on the kind of grout. Particularly, the C1 maximum was observed at around 100 exposure days for silica fume grouts, and at approximately 50 days for CEM I SR grouts. Furthermore, until that age, the capacitance C1 values were very similar for the three analysed grouts. Since then, the greatest capacitance C1 values were observed for SF10 grouts, although this parameter in general showed a similar magnitude for all the grouts studied. After reaching their respective C1 maximums for each grout type, this parameter gradually fell over the remainder of the 600-day period.The capacitance C2 are depicted in 1, the evolution of C2 was very similar regardless of the grout kind, showing a similar magnitude in general across all of the grout types. This parameter rose for approximately 150 days, and decreased afterwards. At early ages, the highest capacitance C2 corresponded to CEM I SR grouts, and this parameter was lower and very similar for both types of silica fume grouts. However, after 100 days, the C2 growth of SF5 grouts tended to stabilise, while the C2 values for SF10 continued increasing, and even overtook those for CEM I SR grouts. In general, the capacitance C2 did not show great differences between the three types of grouts between days 200 and 600, although it was slightly higher for CEM I SR and SF10 grouts than for SF5 grouts.The results for the impedance spectroscopy capacitance CThe results of electrical resistivity obtained for the three types of grouts studied are depicted in The evolution of total porosity for the three kinds of studied grouts is represented in The pore size distributions obtained for CEM I SR, SF5 and SF10 exposed to the sulphate aggressive medium are shown in As for the percentage of Hg retained in the samples at the end of the experiment, see Regarding the mass variation of the grouts produced by contact with the aggressive sulphate medium, the evolution of this parameter over time is depicted in The compressive strength results of the grouts can be observed in 1 and R2 are related to the electrolyte that fills the pores of the sample [In the first instance, with respect to impedance spectroscopy results, both resistances Re sample . Then, t1 is associated only with the percolating pores of the sample [1 obtained for silica fume grouts compared to CEM I SR grouts would indicate that silica fume grouts have a more refined microstructure [1 was slightly higher for SF10 (10% silica fume) grouts than for SF5 grouts (5% silica fume) would suggest that the pore network becomes more refined as the percentage of silica fume increases, which is in accordance with previous studies [The resistance Re sample . The ristructure ,24. More studies .1 increasing rate observed for silica fume grouts could be related to the possible role of Na2SO4 as an activator for the pozzolanic reactions [1 results. The fall in the long-term of this parameter for all the grouts would indicate a loss of solid fraction and pore network refinement. This loss was possibly produced by the formation of expansive products during the sulphate attack [On the other hand, the faster Reactions ,25. As aeactions , and woue attack ,19,21,452 value provides information about all the pores of the sample [1 results. Again, the highest R2 values corresponded to silica fume grouts, which would suggest that their microstructure was more refined than that of the CEM I SR grouts. Furthermore, as also happened with resistance R1, when the silica fume percentage was higher, R2 values were higher, which would corroborate findings regarding the influence of this addition on the pore size distribution of cement-based materials [1 and R2 was their quick rise at early ages. The R2 results also reveal the previously mentioned possible effect of Na2SO4 as an activator for the pozzolanic reactions [The impedance spectroscopy resistance Re sample . Generalaterials ,44. Anoteactions ,25.2 results compared to those obtained for R1. On the one hand, the gap between cement types was higher in relation to R2 values than to those of R1. On the other hand, there was hardly a drop in the very long-term of resistance R2 for all the grouts, while a slightly more noticeable fall was observed for resistance R1. Similar differences between resistances R1 and R2 were obtained in a previous recent authors’ work [1 is associated with the percolating pores of the sample [2 gives information about both the occluded and percolating pores of the sample [1, which would corroborate with its decrease at later stages. Moreover, the initial steps of sulphate attack could be done simultaneously alongside the hydration and pozzolanic reactions, so that no effects of this attack in resistance R1 were observed in the short-term.However, several differences were noted in the resistance Rrs’ work , in whicrs’ work , the dife sample , wherease sample . The sul2 together with the analogous process produced in percolating pores, which also contributes to increasing R2 values. Both would then counteract the probable falling effect in R2 produced by the possible damages to the percolating pores caused by the sulphate attack. This could justify the scarce differences observed in the results of impedance resistances R2 and R1 in the context of this research.On the contrary, the occluded pores would not directly receive the sulphate attack, and this would result in no damages from the attack. Therefore, in these pores the main process that is developed would be the formation of new solid phases as products of clinker hydration and silica fume pozzolanic reactions . This wo1 results  would imply an increase of capacitance C1, which was not observed in the long-term. Despite that, the lower reduction at later stages of capacitance C1 compared to C2 would suggest that the process of closing the microstructure by pores silting was also developed, but to a lesser extent than the breaking of previously formed rough structures on pore surfaces.The capacitance Cmaterial . The rismaterial  as produrs’ work , which sresearch , on the research . Both prThe highest electrical resistivity values were obtained for silica fume grouts, which is coincident with impedance spectroscopy results, as seen in 1. The pore size distributions of the grouts in In relation to mercury intrusion porosimetry, the total porosity hardly differed among the studied grouts, as seen in 2 results.The Hg retained in the specimen after the mercury intrusion porosimetry test gives information related to the tortuosity of the microstructure . GeneralDespite showing similarities with the results obtained by the other techniques used in this research, especially in the short-term, mercury intrusion porosimetry did not detect any deleterious effects of sulphate attack at later stages. Some examples of the lack of coincidence include the lack of drop of porosity, and the lack of loss of pore refinement for all the grouts in the long-term. The only exception was the slight reduction of Hg retained, which was expected in light of impedance spectroscopy results. This fact would corroborate the results observed in the previous works ,26,35 toIn view of that, according to the characterisation of the microstructure of grouts prepared using a sulphate-resisting Portland cement and grouts with silica fume addition in this research, it could be confirmed the hypothesis exposed in the abovementioned previous works ,26,35. TLastly, considering the study of the microstructure of the analysed grouts, and despite the differences among the techniques used, all of them agreed that grouts for micropiles that incorporate 5% and 10% of silica fume, have similar or even better performance in the very long-term in comparison with grouts prepared using sulphate-resisting Portland cement.The period of study also showed a continuous rise in the mass variation of the samples, due to contact with sodium sulphate solution, as seen in Finally, the general growth of the compressive strength for the grouts in the short-term, as seen in The microstructure of 5% and 10% silica fume cement grouts exposed to sodium sulphate medium was more refined than that noted for sulphate-resisting Portland cement grouts during the entire studied period (up to 600 days). Moreover, the pore network of the grouts became more refined as the percentage of silica fume increased.In the short-term, a progressive pore refinement was observed in all the studied grouts, independently of cement type used. This has been related to the development of clinker hydration and silica fume pozzolanic reactions, which form new solid phases.2SO4 as an activator of the pozzolanic reactions of this addition, which would accelerate the new solids formation.The faster increasing rate of the majority of the impedance spectroscopy parameters observed in silica fume grouts, as well as the quicker pore refinement process, could be related to the possible role of Na1 and R2 results in the long-term could be due to the different deleterious effects produced by sulphate attack in the percolating pores, and in the occluded pores of the pore network of the grouts.The differences between the impedance spectroscopy resistances RThe fall at later ages of the majority of the impedance spectroscopy parameters, as well as compressive strength for all the analysed grouts could be probably due to the sulphate attack development.In view of the results obtained, apparently the non-destructive impedance spectroscopy would be the most sensitive technique for detecting the processes developed during the sulphate attack in the microstructure of cement grouts for micropiles with a content of silica fume up to 10% and for grouts prepared with sulphate-resisting Portland cement grouts in the very long-term (up to 600 days). This would confirm the good results obtained in a previous work using this technique for grouts with slag and fly ash exposed to the same aggressive conditions.The Wenner four-point electrical resistivity test and mercury intrusion porosimetry seems to have drawbacks when they are used to measure changes in the microstructure of cement grouts following sulphate attack.Despite noting the microstructural effects of sulphate attack in the studied grouts, apparently it would not create notable damages at the macroscopic scale in the very long-term (600 days), at least with respect to the loss of material.The compressive strength of silica fume grouts was very similar to that observed for sulphate-resisting Portland cement grouts at later ages (365 and 600 days) of exposure to the sulphate aggressive medium.According to the results obtained in this research, micropiles grouts with a content of silica fume up to 10% and exposed to an aggressive medium with a high content of sulphates, have a similar or even better behaviour in the very long-term (600 days), in comparison with grouts prepared using sulphate-resisting Portland cement.The main conclusions that can be drawn from the results previously discussed can be summarised as follows:


Vitamins are first defined in general and the nutritional sources of vitamin B12 are evaluated in particular. Since patients with chronic exposures to toxigenic molds manifest vitamin B12 deficiencies, the role of mycotoxins in vitamin B12 metabolism is assessed, and since vitamin B12 plays important biochemical roles in one-carbon metabolism, the synergistic effects with mycotoxins on humans are reviewed. An outline of the proposed mechanism by which mycotoxins disrupt or interfere with the normal functions of vitamin B12 on one-carbon metabolism is proposed. The overall functions of vitamin B12 as a source of coenzymes, in intracellular recycling of methionine, in methionine synthase reaction, in the prevention of chromosome breakage, in methylation, and in maintaining a one-carbon metabolic balance are reviewed. Signs, symptoms, and clinical neurological indications of vitamin B12 deficiency are also cited. By implication and derivation, it is likely that the interruption of the structure and function of vitamin B12 would in turn interfere with the one-carbon metabolism leading to the neurological manifestations. This review is an attempt to formulate a basis for an ongoing research investigation on the subject.This paper evaluates the possible reasons for consistent vitamin B


To verify the type of milk consumed by children under one year of age and identify variables associated with non-maternal milk consumption (formula or cow milk).  Cross-sectional study developed during the 2012 National Vaccination Campaign against Poliomyelitis. The companions of 935 children under one year of age answered a structured questionnaire on the child’s diet in the last 24 hours. The estimates are presented by points, with 95%CI. F-statistics were used to check for differences in the proportion of the types of milk consumption according to the children’s age range (<6 months and 6-11 months) and the association between non-maternal milk consumption and the study variables.  The consumption of maternal milk and child formula was higher for children under six months of age - corresponding to 82.8% (95%CI 78.5-86.3) and 70.4% (95%CI 61.4-78.0), respectively -, whereas the consumption of cow milk was higher among children between 6 and 11 months of age - 74.2% (95%CI 66.5-80.6) -, with differences in the consumption proportions (p<0.0001). The variables associated with higher cow milk consumption were lower maternal education (p<0.0001), the fact that the mother does not have a paid occupation (p=0.0015), child doctor’s appointment in the public health network (p<0.0001) and participation in the Child’s Milk Program (p<0.0001). The infants received cow’s milk early (before the first year of life), especially children from families with lower socioeconomic levels and children who took part in a specific social program for milk distribuition. The referred program aims at fighting infant malnutrition and encouraging family agriculture. The milk provided is fluid, pasteurized, with minimum 3% fat content and enriched with iron and vitamins A and D.There are few studies about the consumption of types of NMM offered to children aged less than one year, and the variables associated with the consumption of this milk. Therefore, the objectives of this study were to assess the type of milk consumed by children aged less than one year and to identify the variables associated with the intake of NMM (formula or CM).Cross-sectional study conducted during the 2012 National Vaccination Campaign against Poliomyelitis in Guarapuava, Paraná, Brazil. The study population was a group of children aged less than one year who attended the vaccination posts in the urban and rural areas of the city with their parents or guardians.With information about the population of children aged less than 1 year, vaccinated in the first stage of the 2011 campaign, the sample size was calculated using the prevalence of EBF in children aged less than 6 months, with an estimation of 40% being aged between 2 and 3 months, according to a local study,The study used the two-stage cluster sampling.Data collection was conducted between June 11 and 29, 2012, by 118 volunteer students in the courses of Nutrition and Nursing at the local university, who were trained for 4 hours. The data collection instrument was a questionnaire with 67 questions, based on that used in vaccination campaigns from the Breastfeeding and Cities project, from the Health Institute of the Health Secretariat of São Paulo,The variables used in this study were: NMM consumption (formula or CM), maternal age , primiparity (yes or no), maternal schooling , maternal occupation (yes or no), living with the child’s father (yes or no), area of residence , health service the child attends (public network or private/insurance) and participating (yes or nor) of the Children’s milk state program.The descriptive analysis included the calculation of proportions and 95% confidence intervals (CI) for the types of milk consumed by the children. F-statistics was used to identify the variables associated with the intake of NMM and the differences of proportions between the types of milk consumed, using a 5% significance level. To calculate the probability of consumption of the types of milk (breastfeeding (BF), formula, CM and milk from PLC), the logit analysis was used and estimated, by statistical modelling, the probability of the event in relation to the children’s age in days.,This study was approved by the Research Ethics Committee from the Nursing School in Ribeirão Preto, at Universidade de São Paulo (CEP-EERP/USP), report nº 34.613, from June 11, 2012. This study did not require an informed consent form because it consisted of a fast questionnaire applied in the waiting line of the vaccination post. Therefore, the parents or guardians were asked for a verbal consent, in order to not disrupt the vaccination campaign. This procedure was established in the research of the Breastfeeding and Cities project from the Health Institute of the Secretariat of Health in São Paulo and in the II PPAM/Capitals and FD.The participants eligible for the study accounted for 1,118, however, 18 children were excluded for not living in Guarapuava. Sixteen questionnaires were excluded due to inconsistencies in the child’s age, and there were 149 refusals.Of the 935 children who participated in the study, 459 (49.1%) were aged less than 6 months, and 476 (50.9%) were aged 6 months or more; 470 (50.3%) were female, 476 (50.9%) were born from vaginal delivery, and 853 (91.2%) presented with weight at birth ≥ 2,500 grams. Of the total number of children, 86.7% were accompanied by their mothers at the time of the interview. Of the mothers accompanying their children, 45.8% were primiparous; 57.8% were aged between 20 and 24 years; 50.4% had between 8 and 11 schooling years; 61.5% did not work outside the household; and 65.3% took their children to be cared for in the public health network, as described in The variables associated with higher consumption of CM were: lower maternal schooling - with tendency to increase the consumption with the reduction of maternal schooling -, the fact that the mother did not work outside the household, the child being assisted in the public health network and participating in PLC .,,versus 50.5% and 90.9% of the population of reference (SINASC 2011), respectively.Regarding the research design, it is important to mention that the conduction of surveys in vaccination campaigns has been used as a strategy to obtain data of populations in a short period of time, at low cost.,,This study showed that BF (82.8%) and the consumption of formula (70.4%) was higher among children aged less than 6 months, whereas CM (74.2%) and PLC milk (33.7%) were more consumed by children aged between 6 and 11 months. The frequency of the daily consumption of NMM (formula and/or CM) was three times or more for 70.7% of the children analyzed. The intake of CM was high among the studied children, which is opposite to the recommendation of national and international institutions, which do not indicate the intake of this type of milk before the 12 months of life due to its allergenic potential, the protein overload and the high chances of the child developing iron deficiency anemia.It is important to mention that the PLC milk offered to children aged from 6 to 36 months, belonging to families with per capita income lower than half a minimum wage, is the whole CM enriched with iron and vitamins A and D.The suggestion is to conduct a review in the age group of the infant audience to be impacted by PLC, from 6 to 36 months of age to 12 to 36 months of age, besides state and municipal actions defending BF, in order to continue this practice in the first years of life of the children. The relevance of PLC for the rural development and for small and medium-sized producers of the state is recognized and is not being discussed in this paper. However, it is important to think about the implications of CM consumption before the 12 months of life. Another aspect that should be further discussed in this program concerns one of the objectives that elucidates the fight against infant malnutrition, but nowadays the reality points to increasing excess weight among children.A cross-sectional study that analyzed the consumption of milk among Brazilian children aged less than 60 months found that 91.8% of the ones aged less than 6 months were breastfeeding, and 23% used formula; 74.6% of the children aged from 6 to 12 months received CM, and, in the South region, in this age group, 70% consumed more than two milky meals.The probability of children being breastfed and receiving formula in the first days of life was high (around 90%), however, the intake of these types of milk decreases until the end of the first year of life, being more expressive for formula (12%). The chances of CM consumption is inverse, so 50% of the children consumed this milk at the age of 6 months. The consumption of PLC milk increased after the age of 6 months, since after this period the children enrolled in the program start receiving the benefit.A cross-sectional study that analyzed the dietary practices of children aged from 6 to 12 months from 136 cities in the State of São Paulo found that, at the age of 6 months, the probability of a child receiving other types of milk was 70%, and, at the age of 12 months, 83%. However, there is no difference between the types of milk consumed.This study showed that the socioeconomic level influenced the type of milk consumed by the children, since the variables associated with the higher consumption of CM were lower maternal schooling, the fact that the mother did not work outside the household and participating in PLC. There was also a tendency for the increasing consumption of CM with the reduced maternal schooling. The children who attended public health services also consumed more CM. The findings in this study corroborate those of a review article that points low maternal schooling and low socioeconomic status as determinants for the use of unmodified CM.Another study observed that mother with less than eight schooling years, who worked outside the household, had more chances of offering foods from the milk group, including for children aged less than six months.Even though the literature does not show the role of the health service interfering in the type of milk consumed by the children, in this study, the children participating in the PLC should be accompanied every month (weight verification) in the health united as a condition of the program. This suggests an explanation for the fact that the higher intake of CM took place among children who attended the public health network. However, it is worth to mention that despite the association found between the intake of CM and the public health service, this result should be interpreted carefully. A cross-sectional study about the prevalence of breastfeeding in children aged less than two years in Campinas (SP), Brazil, showed that the public health service can have a positive impact on early weaning when compared to the private health system.The importance of BF is consensus in the literature, and children in families with lower socioeconomic status can benefit more from BF, given the impossibility of acquiring formula due to its high cost. The Ministry of Health recommends that if the possibilities of relactation to maintain BF are finished, and at the financial impossibility to acquire formula, professionals should advise mothers as to the adequate and safe use of CM.Some limitations of this study are the non-investigation of how the types of milk consumed were prepared, that is, if they were offered pure, diluted or with the addition of other foods; and the fact that the data were obtained in a single 24-hour recall. The strong aspect of this study highlights the sampling technique used. Further studies are required to verify the impact of the milk offered in the PLC on the nutritional status of the children who receive this benefit, and the influence of the consumption of this milk in the continuity of BF.In this study, the children received CM before the first year of life, especially those from families with lower socioeconomic status inserted in the social program to receive milk.


Nature Communications 10.1038/s41467-017-01286-w, published online 30 October 2017Correction to: The original PDF version of this Article contained an error in Equation 1. The original HTML version of this Article contained errors in Equation 2 and Equation 4. These errors have now been corrected in both the PDF and the HTML versions of the Article.ri was missing, and incorrectly read:The original PDF version of this Article contained an error in Equation 1. A dot over the first occurrence of the variable The correct form of Equation 1 is as follows:This has now been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.The original HTML version of this Article contained errors in Equation 2 and Equation 4.ri replaced the intended dot, and incorrectly read:In Equation 2, a circle over the first occurrence of the variable The correct form of Equation 2 is as follows:ri replaced the intended dots, and incorrectly read:In Equation 4, circles over the first and fifth occurrences of the variable The correct form of Equation 4 is as follows:This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication.


The incidence of type 1 diabetes mellitus in children is highly variable in the world. The aim of our study was to: 1) analyze the evolution of the incidence of childhood type 1 diabetes in Romania between 1996 and 2015, and: 2) to search for differences amongst age groups, gender, geographic regions and month of diagnosis.Data on all new cases of type 1 diabetes, aged <15 years, obtained from two independent sources, were included in the study. The statistical methods included modeling of the incidence rates, adjusting for age, sex, calendar year, geographic region and seasonality.The study group was composed of 5422 children, with overall completeness of ascertainment estimated at 93.7%. The incidence rate (per 100.000 person-years) rose continuously, from 4.7 [95% confidence interval (CI) 3.9-5.7] in 1996 to 11.0 (95% CI 9.9-12.2) in 2015, by a yearly rate of 5.1%, highest in the youngest and lowest in the oldest children. The mean incidence was significantly higher (p<0.0001) in Transylvania  than in Moldavia  and Muntenia , probably due to differences regarding ethnicity and lifestyle. The monthly incidence showed a sinusoidal pattern, peaking in January and being minimum in June.The incidence of type 1 diabetes mellitus in Romanian children increased continuously during the study period by a rate that, if maintained, would lead to its doubling every 14 years. Important differences were established between geographic regions and seasonality at diagnosis. The incidence of type 1 diabetes mellitus is highly variable in the world. Epidemiological data for the EURODIAB Study and the DIAMOND Project were collected in Bucharest, Romania’s capital city. Romania had a low incidence of the disease, but it increased continuously over a 10-year period (2002-2011) in children aged 0-17 years.Our study found a steeper rise in the incidence of childhood type 1 diabetes mellitus than the one reported globally. Romania now belongs with the countries having a high incidence of the disease. There are significant differences between geographic regions and there is a seasonality regarding the diagnosis.Knowledge about the epidemiology of type 1 diabetes mellitus (T1DM) has always been of interest among diabetologists. Epidemiological information is important not only for health care systems, but also for researchers, providing valuable information about the underlying mechanisms of this chronic disease. The currently accepted theory regarding the pathogenesis of T1DM states that, in genetically predisposed individuals, the intervention of some environmental factors triggers the activation of the immune system and leads to beta cell destruction and, consequently, to absolute insulin deficiency .Most of the data regarding the incidence of T1DM concerns children, and they derive from two important multinational studies ,4, as weHowever, the knowledge regarding the secular trend of the incidence is far from being complete, since some data show continued increase ,6, whereRomania was part of the aforementioned multinational studies, but it provided data only from the capital, Bucharest, and its surroundings. In the last two decades, the Romanian Childhood Diabetes Registry was developed, and has provided information from all over the country. According to this source, Romania had a low incidence of the disease, with some regional differences , but theThe aim of this paper is to characterize the evolution of the incidence of T1DM in children aged 0 to 14 years during the 20 years that the Romanian Childhood Diabetes Registry has existed, and to establish the possible differences between various age groups and the two genders, as well as to reveal some regional and seasonal particularities.This retrospective study was conducted on Romanian boys and girls under the age of 15, diagnosed with T1DM between 1996 and 2015. The study was approved by the Ethical Committee of “Victor Babes” University of Medicine and Pharmacy Timisoara . Due to the fact that it was a retrospective epidemiological study, informed consent was not requested.The cases were collected from two independent sources. The primary source was the Romanian Childhood Diabetes Registry. This registry was started in 1996 by ONROCAD , and revised on a yearly basis, relying on the reports of the physicians who were managing these cases. Romania is divided into 41 administrative districts. Medical care for diabetic children is provided in a centralized manner. According to the rules imposed by the National Health Insurance Company, insulin and glucose strips are reimbursed only if prescribed by a limited number of physicians, up to four in each district . Consequently, the primary source of this study was based on the yearly reports of about 70 health care professionals, which included children with T1DM who constituted the majority of the cases compared to other types of diabetes. The records of the “Cristian Serban” Medical Center in Buzias, a public health care center specialized in the diagnosis, evaluation, education and treatment of children and young people with diabetes mellitus from all over the country, considered as a European Reference Center for the management of pediatric diabetes, constituted our second source .The completeness of ascertainment of the cases was calculated by the capture-recapture method , using tThe diagnosis of T1DM was established by the lead physician for each case, based on internationally accepted guidelines . The datThe demographic data was retrieved from the National Institute of Statistics (15). These data were derived from the censuses performed in 1992, 2002, and 2011, also using estimates for the other years. The data were collected for each of the 41 administrative districts, for both genders, and for three standard age groups: 0-4 years, 5-9 years, and 10-14 years.The incidence rates were expressed as new cases per 100.000 person-years at risk, with approximate 95% Poisson confidence intervals (CIs). Poisson regression was used to model the incidence rates, adjusting for age groups, sex, calendar year and geographical region, taking the respective background population into account as exposure.The analysis of seasonality at diagnosis was based on all cases aggregated over sexes and all years, with stratification by age at diagnosis , as well as all ages combined. Using methodology described by Edwards (16), the analysis included a general test for seasonal variation , a test for sinusoidal variation (Cyc. trend), as well as a test for seasonal variation unexplained by lack of fit of the sinusoidal model .After the exclusion of other types of diabetes mellitus, the primary source (the Romanian Childhood Diabetes Registry) identified 5248 cases, whereas the secondary source  provided 1878 cases. Among the total 5422 cases ascertained, 1704 were captured independently by both sources. Based on these data, the total number of patients captured by the two sources was 5422, the number of missed cases was estimated to be 362, and the probable total number of patients was 5784.The overall completeness of ascertainment was 93.7% (95% CI 93.1-94.4)  and constant during the study period (data not shown). The value of the completeness of ascertainment for the primary source was 90.7% (95% CI 89.4-92.1), and for the secondary source 32.5% (95% CI 31.2-33.7).The yearly incidence rate (per 100.000 person-years) showed a continuous increase during the study period, from 4.7 (95% CI 3.9-5.7) in 1996 to 11.0 (95% CI 9.9-12.2) in 2015 , correspThe mean incidence of the disease in the study period was 7.2 (95% CI 7.0-7.4). It was not significantly (p=0.53) higher in boys  than in girls . The differences between the age groups were statistically significant (p<0.0001). The highest incidence was found in the age group 10-14 years , followed by the age groups 5-9 years , and 0-4 years . The mean age at diagnosis was similar in girls and in boys (p=0.81).There were striking differences between geographic regions regarding the incidence of T1DM . The meaThe incidence of T1DM differed by months in a pattern compatible with a sinusoidal variation . The incThe epidemiology of T1DM in Romanian children has been described previously. The first papers included only the capital, Bucharest , this reThe incident cases were retrieved from two sources that diagnose and report new cases of childhood T1DM independently from each other. The primary source was the Romanian Childhood Diabetes Registry, in which records of children with diabetes are included, based on the evidence kept and forwarded by local diabetologists or endocrinologists. The secondary source was represented by the data files of patients admitted to the “Cristian Serban” Medical Center in Buzias, a public hospital where children with diabetes mellitus are admitted if referred by a physician or by direct registration via the diabetes association or website. The overall completeness of ascertainment was high (93.7%), and it was constant over the study period. The primary source had, by itself, a high completeness of ascertainment (90.7%). This could be explained by the fact that the medical care of children with diabetes mellitus is provided by a health system that can be considered centralized, as each of the 41 districts includes only few physicians (up to four) who are in charge of these cases. The relatively low number of physicians facilitates the achievement of almost complete data for the Romanian Childhood Diabetes Registry. The low completeness of ascertainment of the “Cristian Serban” Medical Center in Buzias may be explained by the fact that only a small percentage (about 30%) of all the children with diabetes from Romania benefited from evaluation, education and treatment within this hospital.During the 20 years of follow-up, the incidence of T1DM in children increased constantly, with an annual rate of 5.1%, which is higher than the one reported by the EURODIAB study and the DIAMOND project ,4. Due tSuch a rapid increase in incidence rates usually characterizes countries with lower overall incidence , while iIt is known that Hungary  and GermAnother possible explanation for this steep increase is the shift to a younger age at diagnosis. It is hypothesized that T1DM occurs at a younger age, due to an earlier effect of the environmental triggers, and that the overall incidence of the disease is not changed. This idea is supported by several trials that have analyzed the evolution of the incidence of T1DM in children, as well as in adults , and wasThe highest incidence of T1DM was registered in the age group 10-14. This is the age when most of the children reach puberty. The insulin resistance induced by the release of sex hormones may play an important role in the onset of T1DM . Boys haRomania is composed of three geographic regions , each of them including several administrative districts. Transylvania was, in the past, part of the Austro-Hungarian Empire. Nowadays, its population is more heterogeneous, as compared to Moldavia and Muntenia, the Hungarian and German ethnic minorities being more numerous here than in the other regions.Our study has revealed significant differences between these three regions. The highest mean incidence was encountered in Transylvania, and this was significantly higher compared to Moldavia and Muntenia, respectively. In a previous paper published by our group , an analThe seasonal variability of T1DM underlines the role of infectious triggers and of the deficit of sun exposure in the pathogenesis of the disease ,27. The Our study has revealed significant seasonal variation of the incidence of T1DM, the highest values being recorded during winter (maximum incidence in January), and the lowest during summer (minimum incidence in June). This pattern was seen in children belonging to the age groups 5-9 and 10-14, but not for the youngest ones. The quite constant occurrence of the disease between ages 0-4 could be explained by the decreased exposure to infections, due to country’s specifics: children are raised by their parents in the first two years of life , by their grandparents in the following year. Admission to communities, where infections are more prevalent, usually takes place after the age of three years.Similar data were reported by the EURODIAB investigators  for the Our study has several limitations and strengths. The main limitations are represented by the lack of information regarding the ethnicity of the newly diagnosed patients, a finding that could have facilitated the interpretation of the regional differences in the incidence. The absence of data about the dietary habits in early life and of the population from different geographic regions, as well as the lack of evidence about the evolution of the incidence of diabetes mellitus in adolescents and young adults, a finding that could have supported the theory of the shift towards a younger age at diagnosis, can be listed as other limitations. The strengths of our research consist in the existence of accurate data, provided by two high quality sources that cover the entire territory of the country over a long period.We have analyzed the trends in the evolution of the incidence of T1DM in Romanian children aged 0-14 years, over a 20-year span (1996-2015), taking into consideration some particularities regarding age group, gender, geographic region, and seasonality. We found a steeper rise in the incidence than the one reported globally, for both genders and all age groups and, if this trend were to be maintained, it would lead to a doubling of the incidence every 14 years. Romania now belongs with the group of countries with a high incidence of childhood T1DM. There are significant differences between the geographic regions and there is a seasonality regarding the diagnosis of T1DM that concerns all age groups, except for the very youngest. The shortcomings of the research could be overcome by continuation of follow-up and the addition of new information about adult patients, ethnicity of the subjects and lifestyle with particular emphasis on changes in eating habits.


Computer Assisted Solutions for Studying the Availability aNd DistRibution of novel psychoActive substances) project. In seven snapshots over 12 months, 808 unique vendors were found selling 256 unique NPS. The total number of individual NPS and vendors increased across the data collection period . Only 24% (n = 61) of the total number of NPS and 4% (n = 31) of vendors appeared in every snapshot over the 12 months, whereas 21% (n = 54) of NPS and 45% (n = 365) of vendors only appeared once throughout the data collection. The individual NPS and vendors did not remain the same over the 12 months. However, the availability of NPS and vendors selling NPS grew. NPS consistently available on crypto markets could indicate popular substances.The Internet has played a major role in the distribution of New Psychoactive Substances (NPS), and crypto markets are increasingly used for the anonymous sale of drugs, including NPS. This study explores the availability of individual NPS and vendors on the crypto markets and considers whether crypto markets are a reliable platform for the sale of NPS. Data was collected from 22 crypto markets that were accessed through the hidden web using the Onion Router (Tor). Data collection took place bimonthly from October 2015 to October 2016 as part of the CASSANDRA ( New psychoactive substances (NPS) are an emerging phenomenon, and their representation on the hidden web  is under-researched. The Internet has played a major role in the distribution of NPS, and drug marketplaces  on the hidden web are increasingly used for the anonymous sale of drugs, including NPS ,2,3.The European Union (EU) Early Warning System currently monitors over 650 substances . HoweverOn the hidden web, drugs can be sold and purchased anonymously through crypto markets that use an “eBay”-style system where buyers can publicly review the sellers and therefore build their reputation, attracting future transactions ,12,13,14Crypto markets are increasingly being used for the sale and purchase of drugs, regardless of the instability both the markets and the vendors show. To date, research has not focussed specifically on the lifespan of vendors selling NPS, substances whose popularity and availability are unpredictable. This paper, therefore, aims to explore the lifespan of individual NPS sold on the crypto markets, explore the lifespan of individual vendors selling NPS on the crypto markets, and consider whether crypto markets are a reliable platform for the sale of NPS.Computer Assisted Solutions for Studying the Availability aNd DistRibution of novel psychoActive substances) project [The study was part of the CASSANDRA , name of the vendor selling NPS, and name of the crypto market used by the vendor. Some NPS were sold under various aliases; these were categorised by their most common name. Furthermore, branded NPS that were commonly found on the visible Internet were categorised according to their contents. All analyses were performed using Microsoft Excel 2016 , unless otherwise specified.All users on crypto markets were anonymous. The research was purely observational and did not involve interaction with either buyers or sellers. The study was approved by King’s College London PNM Research Ethics reference number: LRS-15/16-3084 as part of the CASSANDRA project.The total number of individual NPS and vendors increased across the seven snapshots in the data collection period  . Over 12n = 54) of the NPS reported over the 12-month period only appeared in one snapshot (n = 36) of the total number of NPS appeared in two of the seven snapshots. Ten percent (n = 26) appeared in three of the seven snapshots, 7% (n = 18) appeared in four of the seven snapshots, 11% (n = 29) appeared in five of the seven snapshots, and 13% (n = 32) appeared in six of the seven snapshots. In addition, 24% (n = 61) of the total number of NPS appeared in each of the seven snapshots over the 12-month period  appeared only once over the 12-month period (n = 184) of the total number of vendors appeared in two snapshots over the 12-month period, 13% (n = 103) appeared in three snapshots, 8% (n = 63) appeared in four snapshots, 4% (n = 30) appeared in five snapshots, 4% (n = 32) appeared in six snapshots, and only 4% (n = 31) of the total number of vendors appeared in all seven snapshots.Almost half of all vendors (45%, h period . Twenty-The total number of individual NPS and vendors increased over the 12-month duration of the study. Almost half of the total number of vendors had a lifespan of only a few months, and the NPS advertised fluctuated over the study. One-fifth of NPS were available for the entirety of the study, whereas just under one-quarter were only available for a few months before disappearing. From the results of this study, the contents of the NPS market on the crypto markets varied, but a market was consistently available.Research has shown that the use of crypto markets and the availability of substances including NPS have increased in recent years ,20,24. TThis study found that 256 different NPS were available for purchase over the 12 months of the study, and nearly one-quarter of NPS remained available on the crypto markets, suggesting that these substances could be the most popular NPS. The majority of the NPS that were available in every snapshot were cathinones and phenethylamines (categorised according to ,9. It isAlmost half of the vendors were only captured in one snapshot over the course of the data collection, and the number of vendors who appeared in the data reduced as the snapshots increased . These fThis study has several limitations. As this study was exploratory and lacked contact with the vendors, we were unable to verify whether the substances advertised were the same substances being purchased and received by the customers. Because of anonymity, another limitation is that studies like the present one are unable to capture how many vendor profiles are controlled by one person or if the number of vendors that are only available for a few months before disappearing are, in fact, opening and closing various accounts .Online sales hold a predominant portion of the NPS market, and crypto markets are an emerging source of sale. NPS sold on crypto markets should be monitored to track the popularity and availability of specific substances. Our study found that vendors selling NPS had short lifespans, with half of the vendors only appearing once in the data collection. Individual NPS had longer lifespans, however not all NPS were available over the study period; only a quarter of the total NPS were available in all snapshots over the year. Regardless of the fluctuation of the vendors in the NPS market on the crypto markets, the number of NPS and vendors selling NPS increased over the year. The NPS that consistently appeared across the 12 months of data collection may suggest what substances are popular with the consumers. Crypto markets are therefore to be monitored for the sale of NPS, especially in light of the tightening regulations being applied in various countries.


To identify the historical trend of leprosy epidemiological indicators in individuals under the age of 15 in the state of Mato Grosso. Descriptive study with trend analysis of leprosy indicators in individuals under the age of fifteen registered in the Mato Grosso’s System for Notifiable Diseases between 2001 and 2013. We used the Prais-Winsten procedure for analyzing generalized linear regression at a significance level of 5%. We considered as increasing time series when the annual percent change was positive, decreasing when negative and stationary when there was no significant difference between its value and zero. We analyzed 2455 cases of leprosy and the average detection rate in individuals under the age of fifteen was 22.7 per 100 thousand inhabitants. The trend of the general coefficient of incidence was decreasing, with an average annual rate of -5.5% (95%CI -7.5–-3.5). Increasing trend was observed with an increase of 6.7% (95%CI 2.7–10.8) in the proportion of multibacillary cases, 9.4% (95%CI 4.4–14.7) of cases diagnosed with dimorphic clinical form and 14% (95%CI 7.9–20.4) of cases with physical disability level 2 at the time of diagnosis. There was an increasing trend in the average proportion of examined contacts, with a growth of 4.1% (95%CI 1.2–7.1) and average proportion of healing was precarious (39.7%), with stationary trend. The historical trend of leprosy cases in individuals under the age of fifteen proved to be decreasing in the period, however the trends of epidemiological indicators such as the proportion of multibacillary cases, physical disability level 2 and healing, indicate late diagnosis with stay sources of transmission and consequent worsening of the disease in the state of Mato Grosso. Leprosy diagnosis requires careful examination in children, due to the difficulty of applying and interpreting sensitivity testsa.Leprosy predominantly affects the skin and peripheral nerves. The diagnosis is clinical and epidemiological, performed through anamnesis and dermatologic examination to identify lesions or skin areas with altered sensitivity and/or peripheral nerves impairment 26. Polychemotherapy (PCT) is the main strategy for controlling the disease. Three decades after the treatment started, leprosy cases reduced significantly in Brazil and in the world. The disease remains a national public health problemdespite the improvement in the care of assisted leprosy cases, with a consequent incidence reduction26.According to the World Health Organization (WHO), 210,758 new cases of leprosy occurred in the world in 2015. Brazil ranks second in relation to the number of new cases worldwide, with 26,395 records, of which 7.35% were children under 15 years oldb.In 2015, Brazil had 14.06 cases/100 thousand inhabitants, with 4.28 cases/100 thousand inhabitants in the population under 15 years old. Leprosy has a heterogeneous distribution and is hyperendemic in some states, such as Mato Grosso, which presented 93 new cases/100 thousand inhabitants and 21.3 new cases/100 thousand inhabitants in children under 15 years old also in 201521. However, other countries indicated a reduction in leprosy cases in this age group. China (1987-2008) decreased from 186 to 40 cases in absolute number, and Zambia (1991-2009), from 27.3 to 4.3/100 thousand inhabitants25. A Brazilian study  showed general average growth trend over the course of 13 years (1995-2007), with an average of 95 cases per year1.In the last decades, the incidence of registered cases in children maintained or discreetly reduced. An Indian study found that the leprosy incidence in children under 15 years old showed an insignificant decrease from 2003 to 2012, with more cases between two and 15 years oldMycobacterium leprae, active and recent transmission, besides index cases not yet identified and not assisted by the health system26.The strength of morbidity, magnitude and trend of the endemic of the children population is considered the main indicator of the disease monitoring, since it suggests intense circulation of 20. As the risk of a healthy subject developing leprosy increases ninefold when a family member is affected, performing the household contact examination of all newly diagnosed cases23 is recommended. Collective examination is another essential strategy for controlling the disease. One study added 38.2% of cases to spontaneous demand through active school search, indicating that this environment is an institutional area for active leprosy control actions in this population5.The contact of individuals with leprosy in the bacilliferous form is the main source of disease transmission, mainly in the household environment. In endemic countries, the child population generally has early contact with a bacilliferous patientc.Epidemiological indicators, such as the leprosy incidence coefficient in children under 15 years old, the proportion of cure of new cases and the proportion of intradomiciliary contacts of new examined cases, allow us to monitor the extent of disease elimination as a public health problem. In addition, these indicators support the critical analysis of the results and help in the decision-making process, contribute to the continuous improvement of organizational processes, and enable the comparative analysis of performance17.Studying leprosy indicators in children under 15 years is done to understand the magnitude and strength of endemic and health system performance in disease surveillance. Data organization in a time series allows us to analyze the phenomenon, possibly indicating evolution of risks to which people are or have been subjected, providing subsidies for causal explanations, assisting in health planning and evaluating the impact of interventionsAs such, this study aimed to identify the historical trend of leprosy epidemiological indicators in individuals under the age of 15 in the state of Mato Grosso.In this descriptive study, we analyzed the historical trend of leprosy indicators in individuals under the age of 15 reported in the state of Mato Grosso, from 2001 to 2013.17.The historical series is a sequence of quantitative data relating to specific moments and studied according to their distribution in time. It had the purpose of detecting and interpreting the evolution of leprosy indicators during this period17.We obtained information on children less than 15 years with leprosy through a database of the National Notification System of Mato Grosso (SINAN/MT), provided by the epidemiological surveillance department of the State Health Department of Mato Grosso . To select the historical series, we included all the years (2001-2013) available in the SINAN/MT bank until the collection date. A historical series should refer to a period sufficient to enable the researcher to perceive the event trend: whether stationary, ascending or descending. However, the period is generally determined by the data availability, not by the researchera. We excluded the cases considered diagnostic error in the database, with transfer to another state or country, duplicity and data inconsistency. Those excluded due to data inconsistency were the cases with birth date corresponding to the diagnosis date, making up the zero year of age.The historical series analysis included leprosy cases that presented one or more of the following cardinal signs: a) lesion(s) or skin area(s) with altered sensitivity; b) impairment of peripheral nerve(s), with or without thickening, associated with sensory, motor or autonomic alterations; and c) positive intradermal smear microscopyThe variables of interest were the indicators that represent the strength of morbidity and magnitude of leprosy (incidence coefficient in children under 15 years) and the quality of actions and services . The other variables were temporal characters (years), sex, operational classification, clinical form, physical disability at diagnosis and way of detection.b. The incidence coefficients among those younger than 15 years old were classified as: hyperendemic (≥ 10.00); very high (9.99 to 5.00); high (4.99 to 2.50); mean (2.49 to 0.50); and low (< 0.50). The assessments of the proportion of healing and proportion of intradomiciliary contacts of new cases occurred from 2003 to 2013 due to the need of following-up the cohort according to calculation recommended by the Ministry of Healthc. The reference parameters for the healing ratio were good (≥ 90%); regular (89.9% to 75%); and precarious (< 75%). The reference parameters for the proportion of intra-household contacts of new leprosy cases were good (≥ 75%); regular (74.9% to 50%); and precarious (< 50%)a.Leprosy incidence coefficient in the population was estimated (per 100 thousand inhabitants) and calculated according to the relative population of the 2000 and 2010 censuses, in relation to the age group, according to the demographic data of the Brazilian Institute of Geography and Statistics , counting in 1996 and with intercensal projectionsPrais-Winsten procedure for generalized linear regression analysis, since it allows us to estimate the regression coefficients with correction of the first-order temporal autocorrelation2.To characterize temporal trends, we transformed the logarithmic coefficients (Y), as it facilitates to reduce the heterogeneity of the residual variance of the linear regression analysis, that is, the values of the difference between the points of the mean line and points of the time series. In addition, this transformation contributes to determine the annual growth rate. We used the logY(i) = a + bi and logY(i + 1) = a + b(i + 1). The “a” value corresponds to the intersection between the line and the vertical axis and the “b” value correspond to the slope of the line, which was estimated by linear regression analysis. Therefore, by difference: logY(i + 1) - logY(i) = b(i + 1 - i) = b. Thus, we calculated the value of the coefficient “b” and the standard error “EP” of the regression analysis and calculated the annual percent change (APC) and confidence interval (95%CI) using the APC = -1 + 10^b and 95%CI of that rate = -1 + 10^(b ± t * EP), where “t” is the tabulated value of the Student t distribution. When the rate was positive, the time series was considered increasing; when negative, it was considered decreasing; when there was no significant difference between its value and zero, it was stationary2. The software Stata 11.1 performed the statistical analysis.The regression equation of the time series associates the dependent variable with the year. Thus, for each “I” year included in the study period, there is The Research Ethics Committee of the State Health Secretariat of Mato Grosso approved this study, under Opinion 491,444, following all the provisions of Resolution 466/12.From 2001 to 2013, SINAN/MT reported and recorded 2,567 new leprosy cases in children under 15 years old. Of these, we excluded cases with a diagnosis error (n = 65), with a transfer to another state or country (n = 12) and data inconsistency (n = 16), totaling 2,455 registered cases of leprosy in children less than 15 years old in Mato Grosso, with a mean of 188.8 cases per year. The mean coefficient of disease incidence in this age group was 22.7/100 thousand inhabitants in the period.A decrease in the general trend of the disease incidence coefficient occurred, with an APC of -5.5% (95%CI -7.5–-3.5). Males had more pronounced decrease, with an APC of -6.5% (95%CI -8.9–-4.1). However, the overall decrease occurred from 2005 to 2009 .The Among the national leprosy control strategies, defining and monitoring of areas with a higher risk of disease detection are necessary. Although the incidence coefficient trend in children under 15 years old decreased in the studied period in the state of Mato Grosso, it remained hyperendemic, with an increase in multibacillary cases, especially in the dimorphic clinical form. The cases with level 2 physical disability at the time of diagnosis increased, and it was precarious in relation to the healing rate of new cases, with a stationary trend during the analyzed years. These results indicate the recent endemic transmission and deficiency in the care and follow-up of new diagnosed cases until the completeness of treatment.19. For every 100 thousand inhabitants, there were 33.3 cases in 1996-1999, 33.2 in 2000-2003 and 26.7 in 2004-200719. In those years, leprosy hyperendemicity in children under 15 years old indicates bacillus persistence and difficulty of the programs to control the disease. Leprosy is potentially disabling when it affects childhood because of the possibility of deformities; this is a period of growth and development, and can influence school life due to social limitation, discrimination, low self-esteem and stigma. These individuals experience complex feelings and situations in daily life, their routine changes by the limits dictated by the disease and treatment24.A study conducted from 1996 to 2007, in Mato Grosso, also described hyperendemicity in children under 15 years old, with a slight decrease in cases26, as in this study. However, from 1980 to 2003 the state of Espírito Santo showed a significant increasing trend for the coefficients in children under 15 years old (increase of 7% per year)15.Research in other countries has shown recent decrease in the disease trend in this population9.In Mato Grosso, the decreasing trend in the leprosy incidence may be due to the supply of PCT treatment in the health units. Economic growth, improvements in social areas and reversal of the care model for the family health strategy in the last decades may have contributed to the reduction of the local endemic disease22.This decreasing trend was not progressive in the period, concentrating between 2005 and 2009. This probably occurred due to the actions developed by the “Projeto Prioritário Tolerância Zero: Mato Grosso sem hanseníase” (Zero Tolerance Priority Project: Mato Grosso without leprosy) (SES/MT/2001), launched in 2001 with the aim of accelerating activities to achieve the goals of eliminating the disease through financial incentives. This process initially causes an increase in detection for its active search, but it tends to fall due to the reduction in transmissibility resulting from the treatment and healing of the casesd.In that period, the correction in the calculation of the incidence coefficient by the National Leprosy Control Program (PNCH) also occurred, including as new cases only those present in the SINAN database, at federal level, until January 15 of the following year, instead of March 31, as done previously. This operational change favored the modification in the structure of the historical series, producing an artificial fall in the number of new cases19. In the period, control activities were in effect in the state due to the policy of elimination of the disease, and generated a 105.7% increase in units for leprosy diagnosis and treatmente.Some studies suggest that the increase in cases is due to operational improvements in disease control, which increases the diagnoses10.The historical series of multibacillary cases annually increased in 6.7%. The decreasing trend of paucibacillary cases and increasing multibacillary cases suggests late diagnosis. The paucibacillary cases represent initial leprosy phase, which is desirable to conclude the diagnosis, since the bacillary load is low and lack to act as a source of infection, being relevant for endemic control. However, the identification of multibacillary cases, characterized as contagious due to the high bacillary load and the high risk of transmissibility, suggests health services failure4. Completeness is a guarantee of quality information, an ideal condition for the objective analysis of the event under study.The increasing trend of cases defined as ignored as to the clinical form suggests impairment of diagnosis or incompleteness of the data due to lack of preparation or lack of professional commitment. Other studies also observed an increase in the number of fields ignored in the Brazilian epidemiological surveillance system, not identifying significant advances regarding completeness, which generates deficient and unreliable data, as well as interfere in the knowledge of the health-disease process12. Physical disability level 2 indicates the presence of visible lesion and suggests underreporting; it is used to assess the delay of diagnosis and signals to deficiency of health services in the early and accurate detection of cases in children under 15 years old, which may negatively influence social interaction through the increase of stigma and prejudice18.The increasing trend of physical disability level 2 at the time of leprosy diagnosis reflects the disease evolution time, the low effectiveness of early detection and the hidden prevalence26.The improved global strategy for additional reduction of the 2011-2015 leprosy burden emphasized the importance of implementing disease control actions and strengthening training programs for health professionals. Therefore, the improvement of diagnostic activities and the follow-up of leprosy cases, especially in children under 15 years old, favor the reduction of disabilities and inconsistencies in the health information system of the diseaseAs new cases in children may indicate those undiagnosed and not assisted by health units, the trend growth of detecting cases with household contact examination is relevant for the early diagnosis, contributing to the reduction in the transmission of Hansen’s bacillus.a, or both.The average proportion of contacts of these new cases was considered good according to the reference standard. The increasing proportion trend suggests an improvement in epidemiological surveillance activities. On the other hand, the trend of healing proportion was stationary in the period, with a precarious average, possibly resulting from unprepared health services to ensure adherence to treatment until medical discharge or poor quality of follow-up of cases recorded in the SINAN/MT7. This would further increase the size of the disease in the state.We consider the possibility of underreporting of cases, which is due to problems in the flow of receiving information, possibility of errors during data transfer, and lack of completion of investigation and notification formsThe study has other limitation, such as the impossibility of correcting typing errors. In addition, some data in the SINAN/MT may be underestimated, as well as the information of the patient’s monitoring by the health units, which would explain the low average of healing rate.We concluded that in Mato Grosso the leprosy incidence trend in children less than 15 years old in the studied period decreased, but the average detection rate of cases in children less than 15 years remains hyperendemic, with a trend to increase multibacillary cases, the dimorphic clinical form and with physical disability level 2 to the diagnosis. There are conditions for continuous transmissibility of active cases and late detection, and the healing rate is lower the desired, which may culminate in larger transmission outbreaks and the onset of complications such as disabilities and physical deformities.