Among different Aβ species, Aβ25–35 has been identified as the biologically active fragment, as induces major neuropathological signs related to early AD stages. Consequently, it has been extensively used to acutely explore the pathophysiological events related with neuronal dysfunction induced by soluble Aβ forms. However, the synaptic mechanisms underlying its toxic effects on hippocampal-dependent memory remain unresolved. Here, in an in vivo model of amyloidosis generated by intracerebroventricular injections of Aβ25–35 we studied the synaptic dysfunction mechanisms underlying hippocampal cognitive deficits. At the synaptic level, long-term potentiation (LTP) of synaptic excitation and inhibition was induced in CA1 region by high frequency simulation (HFS) applied to Schaffer collaterals. Aβ25–35 was found to alter metaplastic mechanisms of plasticity, facilitating long-term depression (LTD) of both types of LTP. In addition, aberrant synchronization of hippocampal network activity was found while at the behavioral level, deficits in hippocampal-dependent habituation and recognition memories emerged. Together, our results provide a substrate for synaptic disruption mechanism underlying hippocampal cognitive deficits present in Aβ25–35 amyloidosis model.In early Alzheimer disease (AD) models synaptic failures and upstreaming aberrant patterns of network synchronous activity result in hippocampal-dependent memory deficits. In such initial stage, soluble forms of Amyloid- As in transgenic models, acute administration of soluble oligomeric Aβ peptides causes impairments in synaptic plasticity and learning and memory processes [β has a causal role in AD, it is also clear that misfolded oligomeric forms or small Aβ aggregates, and not necessarily plaque formation, are critical in the initial state of synaptic dysfunction in early AD development [β plaques seem to serve as reservoirs of toxic oligomeric fragments that could be released by exposure to biological lipids [β assayed biochemically, than with synapse loss, plaque accumulation, tangle formation, or neurodegeneration [Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by progressive memory loss together with the presence of extracellular amyloid plaques, composed of amyloid-ated tau . The caurocesses . Althougelopment ,4. Aβ pll lipids . In factneration .β contain the sequences Aβ1–40 or Aβ1–42. These peptides have been widely used to create AD models in order to understand the physiopathology of the disease since they have previously been shown to induce long-lasting dysfunctional synaptic plasticity, inflammation, and learning deficits [β25–35, an isoform that can be produced in AD patients by enzymatic cleavage of Aβ1–40 [β [icv.) administration of Aβ25–35.In AD patients, the main oligomeric forms of Adeficits ,8. Howevf Aβ1–40 , constitβ1–40 [β  and is aβ1–40 [β . Consequβ peptides, Aβ25–35 has been shown to induce major neuropathological signs related to early stages of AD [β forms [β isoforms, Aβ25–35 does not generate ion-permeable pores [In similar way to longer Aes of AD . It has [β forms ,15,16,17[β forms  and subj[β forms ,20. Unlile pores ,22 and, β25–35 model, the neurophysiological mechanisms underlying such deficits in vivo, in alert behaving animals, remain unexplored. In the present work, we demonstrate, for the first time, the synaptic and network evidence by which Aβ25–35 induces the main neuropathological effects of early amyloidosis. We show that icv. administration of Aβ25–35 resulted in an alteration of the metaplastic mechanisms that modulate synaptic plasticity threshold induction in the dorsal hippocampus, facilitating LTD instead of LTP. In addition, Aβ25–35 injections disrupted oscillatory activity in CA1 hippocampal region by the generation of an aberrant synchronization of theta and gamma frequencies, neural rhythms needed for learning and memory processes that depend on dorsal hippocampus functionality. Because of both, synaptic and network activity dysfunction, Aβ25–35 showed marked amnesic effects revealed as deficiencies in the formation of hippocampal-dependent memories. Therefore, our results further support Aβ25–35 pathophysiological relevance in vivo and confirm it as a robust model to study metaplastic modulation in hippocampal amyloidosis in relation to memory health, in parallel to other amyloid peptide species models or AD transgenic mice models.Although experimental evidence has demonstrated the presence of learning and memory impairments in An = 5) before surgeries, after which they were placed in individual cages and a piece of environmental enrichment for rodents was provided. They had ad libitum access to food and water throughout all experiments. All animal procedures were reviewed and approved by the Ethical Committee for Use of Laboratory Animals of the University of Castilla-La Mancha (PR-2015-01-01 and PR-2018-05-11), and followed the European Union guidelines (2010/63/EU) and Spanish regulations for the use of laboratory animals in chronic experiments .Experiments detailed in Schaffer collateral/commissural pathway of the dorsal hippocampus . The anesthetic gas was supplied from a calibrated Fluotec 5  vaporizer, at a flow rate of 1–2 L/min oxygen . Mice were implanted with bipolar electrodes aimed at the ipsilateral icv. administration of vehicle or Aβ25–35 to perfuse the dorsal hippocampus [For the pocampus , the selpocampus ). The tiicv. injections during 7 consecutive days (theta (4–12 Hz) and gamma (60–80 Hz) bands were specifically analyzed. The power spectrum of the hippocampal activity was computed with Spike2 software, using the fast Fourier transform with a Hanning window and expressed as mean power spectrum for each frequency band across the sessions [Recording sessions started one week after surgery. The local field potential (LFP) activity and field postsynaptic potentials (fPSPs) were recorded from alert behaving mice with Grass P511 differential amplifiers through a high-impedance probe . LFPs were recorded from the hippocampal CA1 area in the absence of any electrical stimulation, with the behaving animal placed in a small (5  ×  5  ×  5 cm) box before  and after ive days D. Recordsessions ,25.Schaffer collaterals consisted of 100 μs, square, biphasic pulses presented alone, paired, or in trains. fPSP baseline values were collected 15 min before induction of long-term potentiation (LTP) using paired pulses , and the stimulus intensity was set well below the threshold for evoking a population spike, ~35% of the intensity necessary for evoking a maximum fPSP response [For fPSPs, electrical stimuli presented to response ,26. An aSchaffer collaterals evoked a glutamatergic wave with a latency of 2.25–4 ms as the main field excitatory postsynaptic potential (fEPSP) component of the postsynaptic response, closely followed by a field inhibitory postsynaptic potential (fIPSP), GABAA receptor-dependent postsynaptic potential with a latency of 12–15 ms [The different components of the fPSPs analyzed were identified according to their latency of appearance see C. Stimul12–15 ms ,28.β on mice habituation learning, as previously described [icv. drug injection . A square open field arena with an area of 40 × 40 cm and walls 30 cm high was used. A mouse was placed in the center and was allowed to move freely for 15 min while being recorded by a video camera mounted above the open field with an actimeter AC-5 . The recordings were scored later by a motion-recognition software  that detects and analyzes mouse movements ). At the end of each trial the surface of the arena was cleaned with 70% ethanol.The open field habituation task was carried out to determine the effect of Aescribed . Brieflyicv. injection on day 3. Experiments were performed by an observer blind to the treatment condition of the animals. Stimulus objects were made of plastic. There were several copies of each object, which were used interchangeably. The role (familiar or novel), as well as the relative position of the two stimulus objects, were counterbalanced and randomly permuted for each experimental animal. The open-field arena and the stimulus objects were cleaned thoroughly with 70% ethanol between trials to ensure the absence of olfactory cues. Exploration was defined as sniffing or touching the stimulus object with the nose and/or forepaws. Sitting on or going around the objects was not considered exploratory behavior. A video camera was positioned over the arena and the behavior of the mice was recorded using a video tracking and analysis system.To further evaluate learning and memory capabilities in our in vivo mouse model of amyloidosis, object recognition experiments were conducted in an open-field arena (30 × 25 × 20 cm) built of polyvinyl chloride plastic, plywood, and transparent acrylic. The outside walls of the box were covered with metal plates, connected to ground, and the box was placed inside the set-up rack. Experiments were designed to test both short- and long-term memories as previously described . Animalsicv. injection was administered 1 h before the test session. A total of six trials were performed using an acceleration protocol from 4 to 40 rpm over a 5 min period. On each trial, the latency to fall from the rod was measured automatically. The apparatus was cleaned with 70% ethanol between trials.General motor function and coordination were assessed by a rotarod apparatus  with automatic timers and falling sensors . Mice weicv. injection . Mice were placed in the center of a cage and allowed to freely explore for 15 min. During this period, the travelled distance was automatically recorded by a LABORAS® system  based on the detection of vibrations of the movements of each mouse [® cage built of Plexiglas (40 × 23 × 4 cm base and 40 × 23 × 11 cm top). The arena was cleaned with 70% ethanol between trials to remove odors.Locomotor activity was determined by exposure to an open field arena consisting of a rectangular empty cage (40 × 23 cm arena). Animals underwent a single test session 1 h after ch mouse . Data weβ pathology in the dorsal hippocampus in vivo, we used a non-transgenic model consisting of icv. microinjection of Aβ25–35 peptide that mimics the main hallmarks of different amyloidosis models of Aβ [β25–35 peptide was prepared as previously described [β group received 9 nmol of Aβ25–35 (3 nmol/µL) in 3 µL of vehicle solution according to [All chemicals used in this study were purchased from Bachem  and dissolved in PBS (vehicle). To model focal Als of Aβ ,29. Aβ25escribed ,16,30,31rding to , while trding to ,24,27.To verify the proper location of implanted electrodes and cannulas, at the end of the experiments mice were deeply anesthetized  and perfused transcardially with saline followed by 4% paraformaldehyde in phosphate-buffered saline . Their brains were removed and cryoprotected with 30% sucrose in PB. Coronal sections (50 µm) were obtained with a sliding freezing microtome  and stored at −20 °C in 30% glycerol and 30% ethylene glycol in PB until used. Selected sections including the implanted sites were mounted on gelatinized glass slides and stained using the Nissl technique with 0.1% toluidine blue to determine the location of stimulating and recording electrodes and/or the implanted cannula A,B, as pRecordings were stored digitally on a computer through an analog/digital converter (CED 1401 Plus). Data were analyzed off-line for quantification of LFPs and fPSPs, using the Spike2 (CED) program and the video capture system. Since synaptic responses did not show contamination by population spikes, the amplitude  of 15 successively evoked fPSPs was computed and stored for later analysis. These computed results were processed for statistical analysis using the figures that were prepared using SigmaPlot 12.0 package  and CorelDraw X8 Software.t test or the repeated measured two-way ANOVA, with time and treatment as within- and between-subjects factors respectively, and with a contrast analysis for a further study of significant differences. For repeated measures two-way ANOVA, Greenhouse Geiser correction was used and indicated in the text when sphericity was not assumed. Statistical significance was set at p < 0.05.Unless otherwise indicated, data are represented as mean ± SEM. All calculations were performed using SPSS version 20 software . When the distribution of the variables was normal, acquired data were analyzed with the two-tailed Student’s β25–35 model. Here, to further investigate the effect of Aβ25–35 on CA3-CA1 synaptic plasticity in behaving animals, each animal received an HFS at Schaffer collaterals and evolution of the fPSPs  = 4.125, Greenhouse-Geisser correction, p = 0.047) with a value of 126.2 ± 11.4% of the baseline for the first pulse (p > 0.05). On the other hand, Aβ-treated mice not only failed to show potentiation of this synaptic plasticity, but presented a progressive depression of these excitatory components that became significant on day 4  = 4.8, p < 0.001; n = 7, F = 2.078, p = 0.021; As expected, LTP of the glutamatergic component was induced only in vehicle-injected control mice  = 4.427, Greenhouse-Geisser correction, p = 0.029, n = 8, 172.2 ± 30%, F = 4.091, p < 0.001, A activation was also induced by Aβ after the HFS protocol  = 4.935, p < 0.001; second pulse, n = 7, 79.4 ± 10%, F = 2.748, p = 0.014; β has a high capability for disrupting the threshold for LTP/LTD induction and consequently, upstreaming learning and memory processes that depend on hippocampal CA3-CA1 synaptic plasticity phenomena.Potentiation of synaptic inhibition was also evaluated for the IPSPs mediated by GABAtivation B. The HFβ-injected mice presented a sustained qualitative increase of the spectral power for low and the rest of the minor cha high frequencies that lasted at least for 6 days, indicating that Aβ is able to synchronize hippocampal oscillatory activity in a wide range of frequencies. More concretely, a quantitative spectral analysis also revealed that Aβ significantly altered theta  = 31.090, Greenhouse-Geisser correction, p < 0.001) and gamma  = 75.115, Greenhouse-Geisser correction, p < 0.001) bands  bands D,E alongβ25–35 not only altered LTP/LTD induction mechanisms  = 5.494, p < 0.001; Aβ25–35, n = 11, F = 7.643, p < 0.001). As shown in p > 0.05 in all trials) or the whole session  = 0.935, p = 0.346), suggesting the absence of any locomotor dysfunction associated to Aβ25–35 administration. Consistently, the locomotion test run in an open field arena revealed similar travelled distances in Aβ-  and vehicle-injected (control) mice  when exposed to an empty chamber (t(18) = 0.409, p = 0.687), further confirming comparable health and locomotor states. On the other hand, the open field habituation test allowed us to evaluate an elementary form of non-associative hippocampal-dependent learning [n = 18; XYZ axis, t(16) = 1.214, p = 0.242; XY axis, t(16) = 1.341, p = 0.199; Z axis, t(16) = −1.712, p = 0.106). 24 h later, on the retention (habituation) trial performed after the injections, only control-vehicle animals significantly decreased their exploratory movements in comparison to the training session, showing they were able to remember the open field (t(9) = 8.074, p < 0.001; XY axis, t(9) = 7.982, p < 0.001; Z axis, t(9) = −0.718, p = 0.491). However, the slight decrease in exploration observed in Aβ25–35-injected animals was not significant (t(7) = −1.848, p = 0.107; XY axis, t(7) = 1.764, p = 0.121; Z axis, t(7) = −0.416, p = 0.690) and evident differences in total and horizontal activity were found when compared to vehicle-injected control mice  = −4.047, p < 0.001; XY axis, t(16) = −3.919, p = 0.0012; Z axis, t(16) = 0.305, p = 0.764), indicating hippocampal-dependent habituation memory deficits induced by Aβ25–35.Our results showed that Achanisms  but alsochanisms  in alertchanisms . Additioβ would also induce long-lasting behavioral deficits. In order to assess hippocampal-dependent memory impairments, we tested mice in the novel object recognition (NOR) test , indicating that mice did not present preference for any object since they spent a similar amount of time exploring both of them.We then asked whether AOR) test B. It is n = 5): DI = 0.25 ± 0.09, t(4) = 2.797, p = 0.049; Aβ (n = 6): DI = 0.44 ± 0.14, t(5) = 3.173, p = 0.025). 24 h later, animals were icv. injected and exposed to two new sessions . Vehicle-injected control mice exhibited positive discrimination toward the novel object (t(4) = 9.291, p < 0.001; NOR 3, DI = 0.37 ± 0.09, t(4) = 4.069, p = 0.015) whereas Aβ-injected animals explored both objects equally (t(5) = −0.636, p = 0.553; NOR 3, DI = 0.007 ± 0.14, t(5) = 0.32, p = 0.976). These results confirm the behavioral correlate of the hippocampal synaptic plasticity impairments induced by Aβ.However, in NOR1 session performed 3 h later, both experimental groups showed more interest for the new object, reflected as higher DI than that observed during training  theory of synaptic plasticity that suggests the necessity of a particular threshold for LTP induction [β1–42 [β25–35 [β25–35 would alter the GABAA-dependent potentiation of fIPSP as it also depends on NMDARs activation [2+ concentration [2+ influx are assumed to generate LTP, whereas lower changes promote LTD [These results, as well as current Anduction . Synaptinduction . Hence, nduction . For exan [β1–42 ,47 or Aβ [β25–35  seems to [β25–35 ,48. It wtivation . Indeed,ntration ,49 that mote LTD . Thus, amote LTD .β can facilitate the induction of LTD generated by low frequency stimulation (LFS). This LTD is mediated by both mGluRs [β-induced LTD, on NMDARs [β causes a dopamine depletion that modifies the threshold for the induction of cortical LTP and/or LTD [On the other hand, it has been shown that Ah mGluRs ,52 or NMh mGluRs ,54 pathwh mGluRs . Indeed,n NMDARs . As we rd/or LTD . This prd/or LTD  and hippd/or LTD  and AD pd/or LTD .β25–35 on dorsal hippocampus-dependent memory, i.e., the transformation of excitatory and inhibitory LTP synaptic response into LTD according to metaplasticity processes predicted by BCM theory of synaptic plasticity, as it has been previously described for Aβ1–42 [β25–35 [β25–35 in cortical L2/3 pyramidal cells [Then, at the synaptic level, our results provide a new substrate to explain the effects of Ar Aβ1–42 ,43. In t [β25–35 , or redual cells , might dal cells ,61, resual cells ,24,27.β-induced hyperexcitability triggers progressive epilepsy and cognitive impairments in AD [theta and gamma bands that occur in early AD have been proposed as potential predictors for the disease [theta power may be the first change in patients with dementia due to AD [theta and gamma powers as found in the present work, suggesting that Aβ25–35, as Aβ1–42 [One of the main contributors to network dysfunction in amyloidosis is the early neuronal hyperexcitability . Aβ-induts in AD ,63. Thes disease ,65. In fue to AD , and couue to AD . These fs Aβ1–42  or transs Aβ1–42 ,68 modelicv. injection of Aβ25–35 presents numerous and key aspects of amyloid toxicity. Deficits in hippocampal spatial memory, evaluated by using different mazes [β25–35 in the dorsal hippocampus that we reported here? To answer this question, among different behavioral tests that have been well correlated with in vivo LTP recording at the CA1-CA3 synapse, open field habituation test and NOR task were chosen. Previously, the rotarod and locomotion tests allowed us to discard unpredictable effects of Aβ25–35 injections on locomotor function, minimizing potential biases in hippocampal-dependent behavioral tasks. The open field habituation test was selected because LTD has been proposed to play a relevant role in hippocampal-dependent learning [β25–35 caused deleterious effects on both tests, suggesting that hippocampal alteration affects habituation and recognition memory formation. It is interesting to note that the same alterations have been clearly described in transgenic mouse models of AD overexpressing Aβ, such as hAPP mice [β1–42icv. injections [theta and gamma bands. Both oscillatory rhythms have been shown to be altered in amyloidosis models as a consequence of the hyperexcitability induced by Aβ25–35 [theta–gamma coupling and facilitate memory processes [It is also well recognized that the non-transgenic model of amyloidosis generated by nt mazes ,69,70, ont mazes , have bent mazes . Howeverlearning , mainly learning  and mechlearning ,74 and tlearning ,54,75. Olearning  and rodelearning . Aβ25–35APP mice ,78 as wejections ,24. In t Aβ25–35 ,60. Evenrocesses . Alteratrocesses .β25–35-mediated deleterious synaptic mechanism that impairs metaplasticity processes needed for memory storage. Such alteration modifies the threshold for LTP/LTD induction, impairs neural network activity, and underlies memory alterations that depend on dorsal hippocampus. These effects resemble those found in transgenic mice with amyloid overexpression or induced by other peptide species where metaplastic activation of hippocampal receptors or channels, such as ryanodine [In summary, our results have shown the presence of an Ayanodine  or GirK yanodine ,24 respe


Many indices of heart rate variability (HRV) and heart rate dynamics have been proposed as cardiovascular mortality risk predictors, but the redundancy between their predictive powers is unknown.SD of normal‐to‐normal R‐R interval (SDNN), very‐low‐frequency power (VLF), scaling exponent α1, deceleration capacity (DC), and non‐Gaussianity λ25s were calculated. The values were dichotomized into high‐risk and low‐risk values using the cutoffs reported in previous studies to predict mortality after acute myocardial infarction. The rate of multiple high‐risk predictors accumulating in the same person was examined and was compared with the rate expected under the assumption that these predictors are independent of each other.From the Allostatic State Mapping by Ambulatory ECG Repository project database, 24‐hr ECG data showing continuous sinus rhythm were extracted and 1, and λ25s values were 2.95, 2.75, 5.89, 15.75, and 18.82%, respectively. The observed rate of subjects without any high‐risk value was 66.68%, which was 1.10 times the expected rate (60.74%). The ratios of observed rate to the expected rate at which one, two, three, four, and five high‐risk values accumulate in the same person were 0.73 times (24.10 and 32.82%), 1.10 times (6.56 and 5.99%), 4.26 times (1.87 and 0.44%), 47.66 times (0.63 and 0.013%), and 1,140.66 times (0.16 and 0.00014%), respectively.Among 265,291 ECG data from the ALLSTAR database, the rates of subjects with high‐risk SDNN, DC, VLF, αHigh‐risk predictors of HRV and heart rate dynamics tend to cluster in the same person, indicating a high degree of redundancy between them. Additionally, following the Ethical Guidelines for Medical and Health Research Involving Human Subjects , the purpose and information utilized in this project have been public through the project's homepages  by medical facilities and were referred for analysis to three ECG analysis centers  located in Tokyo, Nagoya, and Sapporo in Japan. The data were anonymized by the centers and stored with accompanying information, including age, sex, and recording date, time, and location . Table All data were recorded with the Cardy series of Holter ECG recorders , by which multi‐channel ECG data were digitized at 125 Hz with 10 bit (0.02 mV/digit). The digitized data were sent to the analysis centers and analyzed with Holter ECG analyzers ; the temporal positions of all R waves were determined, the rhythm annotations were given to all QRS complexes, and all errors in the automated analysis were corrected manually by skilled medical technologists. The suspicious outcomes of the analysis have been reviewed by contracted cardiologists.2.2From the ALLSTAR database, 24‐hr ECG data were selected for this study with the following criteria.Subject age at ECG recording >20 yearThe first ECG recording, if there was a repeated recordingRecord length >21.6 hr (90% of 24 hr), andCardiac rhythm is in sinus rhythm for >19.2 hr (80% of 24 hr).Data were included only if all of the following were met:Evidence of artificial pacemaker implantation orNon‐sinus rhythm beats >20% of total recorded beats.Data were excluded if ECG showed at least one of the following:2.3iNN} = {itN − itN−1}, where itN represents the time of occurrence of the i‐th normal sinus beat were derived. For the time domain HRV indices, SDNN was computed as 24‐hr standard deviation of iNN and DC was computed by the phase rectified signal averaging of the 24‐hr N‐N interval time series . The power spectral density was integrated for the power within the VLF band (0.0033–0.04 Hz). The VLF power was transformed into a natural logarithmic value to normalize the distribution. For the nonlinear indices, we calculated the fractal correlation properties of HR dynamics using the DFA method and measured the short‐term (4 to 11 beats) scaling exponents(α1)  according to the previous study  were calculated and the similarities between them were defined as (1 − |r|). To visualize the inter‐relationships, a relationship map of the predictors, where the distances between them best match with the similarities between them, was obtained by exhaustive computer searching through all possibilities. The mutual independency of predictors was also assessed by the squared multiple correlation coefficient (R2) calculated by multiple regression analysis of predictor with all other predictors as explanatory variables.To assess the relationships between the predictors, Pearson's correlation coefficients (2.52)  was used for statistical analyses. The Freq, Corr, and Reg procedures were used for assessing occurrence rates, correlation coefficients, and multiple correlations, respectively. 33.1SD) years, 116,554 males, and 148,737 females.From 405,911 ECG data in the ALLSTAR database of subjects aged ≥ 20 years, 84,591 (20.84%) were excluded due to repeated recordings. Of the remaining 321,220 data, 21,014 (6.54%) due to insufficient data length, 20,034 (6.23%) due to atrial fibrillation or flatter, 13,658 (4.25%) due to frequent > 20% ectopic beats, and 1,323 (0.41%) due to implanted pacemaker were excluded, and 265,291 data that met all criteria were finally used in this study. Subjects of the used data were aged 65 ± 16 , whose small values represent independence from the others, were the smallest for λ25s and the largest for VLF.Table Figure 3.3Table 1, or λ25s was lower than the expected rate.Table 41, and negative correlations of λ25s with the other predictors. The inter‐relationships were able to be visualized by a relationship mapping of predictors  and quantity (SDNN and VLF) of HR fluctuations are separated in the upper left and lower right, and those that reflect sympathetic (λ25s)   project that has been approved by the Ethics Review Committee of Nagoya City University Graduate School of Medical Sciences (No. 709).The authors declare no conflict of interest.All authors have read and agreed to the published version of the manuscript. Contributed to conceptualization: E.Y. and J.H.; Contributed to methodology: J.H.; Contributed to software: J.H.; Contributed to validation: E.Y., N.U., and M.K.; Contributed to formal analysis: E.Y.; Contributed to investigation: M.K.; Contributed to resources: N.U.; Contributed to data curation: N.U.; Contributed to writing—original draft preparation: J.H.; Contributed to writing—review and editing: E.Y.; Contributed to visualization: J.H.; Contributed to supervision: J.H.; Contributed to project administration: J.H.; Contributed to funding acquisition: J.H.


To evaluate the usefulness of the retinal sensitivity in branch retinal vein occlusion (BVO) with macular edema (ME) following the anti-vascular endothelial growth factor (anti-VEGF) treatment.Best-corrected visual acuity (BCVA), microperimetry, and optical coherence tomography (OCT) measurements were carried out in 20 patients with BVO with ME, at baseline and 1 month after the anti-VEGF treatment. The relationships among BCVA, mean retinal sensitivity (MS), macular volume (MV), central retinal thickness (CRT), integrity of ellipsoid zone (EZ), mean retinal sensitivity in the most affected quadrant (qMS), and macular volume in the most affected quadrant (qMV) were investigated. In addition, the relationships among the change in BCVA at 1 month (ΔBCVA1m), mean sensitivity in the most affected quadrant at 1 month (ΔqMS1m), MV in the most affected quadrant at 1 month (ΔqMV1m), and CRT at 1 month (ΔCRT1m) were analyzed. The optimal model for BCVA at 3 months after the treatment (BCVA3m) was identified.p = 0.058) between at baseline and after the treatment, but there were significant differences in MS, MV, CRT, qMS, and qMV (p < 0.05). There was a significant relationship between ΔqMS1m and ΔMV1m, ΔCRT1m, and ΔqMV1m, respectively. ΔMS1m or ΔqMS1m and BCVA at baseline and ΔBCVA1m were selected as explanatory variables in the optimal model for BCVA3m.There was not a significant difference in BCVA (paired Wilcoxon test, Retinal sensitivity was related to retinal structure, whereas this was not the case with BCVA. In addition, retinal sensitivity was useful to predict BCVA after anti-VEGF therapy. Retinal vein occlusions (RVOs) are one of the most common retinal vascular diseases . In RVOsThe MP-3 microperimeter  is a relatively new perimetry instrument. In contrast to its predecessor of the MP-1, the MP-3 has a wide dynamic range (between 0 and 34 dB) on the background luminance of 31.5 ASB which is identical to that with the HFA. Furthermore, in this microperimeter, the target light is projected onto the retina directly, rather than on a screen like in the HFA, which enables automatic tracking of retina. As a result, the exact same location can be stimulated in repeated target presentations. We previously reported visual retinal sensitivity measured with MP-3 has a better test-retest reproducibility than HFA in patients with retinitis pigmentosa (RP)  and glauThis was a retrospective study and the procedures were approved by the Research Ethics Committee of the Graduate School of Medicine and Faculty of Medicine at The University of Tokyo (#3770). Written consent was given by patients for their information to be stored in the hospital database and used for research. This study was performed according to the tenets of the Declaration of Helsinki.This study included 20 eyes of 20 consecutive BVO patients . All patients were major BVO not macular BVO. Five patients underwent 0.5 mg of ranibizumab intravitreal injection whereas 15 patients were given the injection of 2 mg of aflibercept. Seventeen eyes had already received anti-VEGF treatments 3.95 times  on average prior to the initiation of the current study.Each patient had received one injection followed by the pro re nata phase (1 + PRN regimen) when the central macular thickness was greater than 250 μm.All patients enrolled in the study fulfilled the following criteria: (1) BVO was the only disease-causing VF damage; (2) no other treatments for ME, such as laser photocoagulation, intraocular surgery, and intravitreal steroid injection, were performed prior to the initiation of the current study and also during the follow-up period; (3) refractive error between − 6 and + 6 diopter (D); (4) no obvious ischemic changes in macula confirmed using OCT angiography .BCVAs (LogMAR) were measured at baseline and 1, 3, and 12 months after the anti-VEGF treatment .Spectral domain (SD) OCT measurement was performed using the Spectralis OCT at baseline and 1 month after the anti-VEGF treatment. The OCT images consisted of line scans , raster scans, and topographic mapping. Line scans were created by taking the average of 100 B-scans (768 A-scans per B-scan) within 30°. The raster scan was performed using 25 B-scans (768 A-scans per B-scan) of a 30° × 20° area. Then, the average of the central retinal thickness (CRTbase: at baseline and CRT1m: at 1 month after anti-VEGF treatment) and macular volume (MVbase: at baseline and MV1m: at 1 month after anti-VEGF treatment) were calculated. Furthermore, MV in the most predominantly affected quadrant was calculated (qMVbase: at baseline and qMV1m: at 1 month after anti-VEGF treatment). The most predominantly affected quadrant was initially identified by an examiner (R.F.), followed by verification by an independent examiner (T.I.). If the second estimator did not agree with the first examiner, a panel discussion  was held to draw a conclusion. The OCT images of a representative case reflecting the MV and qMV at baseline and 1 month after anti-VEGF treatment are shown in Fig. MP-3 measurement was conducted at baseline and 1 month after anti-VEGF treatment. All patients had a pupil size larger than 4 mm in diameter, as required for the MP-3 measurement. The MP-3 measurement was carried out using the 4–2 full threshold staircase strategy using the standard Goldmann III stimulus size on the background luminance of 31.4 ASB. The maximum luminance of the MP-3 is 10,000 ASB, which results in the stimulus dynamic range between 0 and 34 dB. Eccentric circle was drawn at 2, 4, and 6° from fovea and eight test points were allocated on each circle, in addition to fovea . In addition, the mean sensitivity in the quadrant corresponds to qMV was also calculated . The differences of these values between baseline and 1 month after anti-VEGF treatment were calculated (ΔMS1m and ΔqMS1m).Comparisons of numerical values between two groups were performed using the paired Wilcoxon test. The relationships between (1) CRTbase and the variables of BCVAbase, MSbase, and qMSbase; (2) CRT1m and the variables of BCVA1m, MS1m, and qMS1m; (3) MVbase and the variables of BCVAbase, MSbase, and qMSbase; (4) MV1m and the variables of BCVA1m, MS1m, and qMS1m; (5) qMVbase and the variables of BCVAbase, MSbase, and qMSbase; (6) qMV1m and the variables of BCVA1m, MS1m, and qMS1m; (7) ΔCRT1m and the variables of ΔBCVA1m, ΔMS1m, and ΔqMS1m; (8) ΔMV1m and the variables of ΔBCVA1m, ΔMS1m, and ΔqMS1m; and (9) ΔqMV1m and the variables of ΔBCVA1m, ΔMS1m, and ΔqMS1m were investigated using the linear regression model.n candidate models and the AICc values of those models are AIC1, AIC2, AIC3, ..., AICn. If AICmin is the minimum of these values, then exp.((AICmin − AICi)/2) describes the relative probability that the ith model minimizes the information loss  [Also, the relationship between BCVA3m and the variables of BCVAbase, ΔBCVA1m, MSbase, ΔMS1m, integrity of EZ, the frequency of the injection of anti-VEGF, and age was investigated using the multivariate linear regression model. Then, the optimal linear model was selected according to the second-order bias-corrected Akaike Information Criterion (AICc) index. Similar analysis was carried out using the variables of BCVAbase, ΔBCVA1m, qMSbase (instead of MSbase), ΔqMS1m (instead of ΔMS1m), integrity of EZ, the frequency of the injection of anti-VEGF, and age. The AICc is the corrected form of the common statistical measure of AIC. AICc gives an accurate estimation even when the sample size is small . In a mu model”)  Relative3. CRTbase was 330.6 ± 135.2 (164 to 622) μm. qMSbase was 19.6 ± 3.3 (12.8 to 26) dB. qMVbase was 1.0 ± 0.24 (0.73 to 1.6) mm3. Among 20 eyes, qMV was in the superior quadrant in 8 eyes, whereas it was in the inferior quadrant in 12 eyes.Table p = 0.058, paired Wilcoxon test). However, significant differences were observed between BCVAbase and BCVA3m (p = 0.033) and between BCVAbase and BCVA12m (p = 0.002). On the other hand, there was a significant difference between MSbase and MS1m, MVbase and MV1m, CRTbase and CRT1m, qMSbase and qMS1m, and qMVbase and qMV1m .There was not a significant difference in BCVAbase and BCVA1m  and between BCVAbase and qMSbase . Although a significant correlation was not observed between BCVA1m and MS1m , there was a significant relationship between ΔBCVA1m and ΔMS1m  and ΔBCVA1m and ΔqMS1m .There was a significant negative relationship between BCVAbase and MSbase . The relationships between CRT1m and the variables of BCVA1m, MS1m, qMS1m, and age are also shown in Table p = 0.0093, linear regression). There was no parameter significantly related to MV1m.Table p = 0.033, linear regression). There was no parameter significantly related to qMV1m.As shown in Table p = 0.053 and 0.17, linear regression, respectively). Similar result was obtained with the multivariable regression analysis . Similar result was obtained with the multivariable regression analysis (Table p = 0.0024), between ΔqMS1m and ΔCRT 1 m , and between ΔqMS1m and ΔqMV1m . Similar result was obtained with the multivariable regression analysis  + 0.76 x ΔBCVA1m  − 0.022 x ΔMS1m : AICc = − 42.1. Removing ΔMS1m from this optimal model resulted in a significant decrease of the loglikelihood .As a result of AICc model selection for BCVA3m using the variables of BCVAbase, ΔBCVA1m, MSbase, ΔMS1m, integrity of EZ, the frequency of the injection of anti-VEGF, and age, only BCVAbase, ΔBCVA1m, and ΔMS1m were selected in the optimal model for BCVA3m: BCVA3m = 0.036 + 0.88 x BCVAbase  + 0.79 x ΔBCVA1m  − 0.014 x ΔqMS1m : AICc = − 41.0. Removing ΔqMS1m from this model did not result in a significantly decreased log-likelihood, although it approached a significance .As a result of AICc model selection for BCVA3m using the variables of BCVAbase, ΔBCVA1m, qMSbase (instead of MSbase), ΔqMS1m (instead of ΔMS1m), integrity of EZ, the frequency of the injection of anti-VEGF and age, only the optimal model was BCVA3m = 0.041 + 0.90 x BCVAbase . This reason for the contradicting result is entirely unknown, but in the current study, BVO patients were consecutively recruited and the majority of patients had already received anti-VEGF treatments prior to the initiation of the study. In contrast to BCVA, MS and qMS significantly improved at 1 month after anti-VEGF treatment, suggesting retinal sensitivity might improve earlier than BCVA.There have been many studies which suggested the usefulness of the anti-VEGF therapy in eyes with BVO with ME –8, 15–19Sugimoto et al.  suggesteOne of the possible limitations of the current study was that the onset of BVO was not known in all patients, and the period from onset was not included in the analysis. The second limitation of the current study was the exclusion of the eyes with ischemic cases. Manabe et al. reported the association between parafoveal capillary nonperfusion and retinal sensitivity in eyes with resolved BVO patients. They concluded mean retinal sensitivity at the capillary non-perfusion area was significantly lower than that at the capillary perfusion area . It woulIn conclusion, there was a significant improvement in retinal sensitivity measured with MP-3 microperimetry in BVO patients with ME, whereas no improvement was observed in BCVA at 1 month after anti-VEGF injection. Retinal sensitivity measured with MP-3 was closely related to the OCT-measured structural change after the anti-VEGF treatment, whereas this was not the case with BCVA. The current results suggest the usefulness of the evaluation of the retinal sensitivity in eyes with BVO and ME.


Grain Zn content in wheat improved from 28.96 to 36.61 mg·kg−1 and that in flour increased from 10.51 to 14.82 mg·kg−1 after Zn fortification. Furthermore, Zn content varied in the different processed components of wheat; that is, Zn content was 12.58 mg·kg−1 in flour, 70.49 mg·kg−1 in shorts, and 86.45 mg·kg−1 in bran. Zinc content was also different in wheat-derived foods, such as 13.65 mg·kg−1 in baked food, 10.65 mg·kg−1 in fried food, and 8.03 mg·kg−1 in cooking food. Therefore, the suitable Zn fortification, appropriate processing, and food type of wheat are important to meet people's Zn requirement through wheat.Improving zinc (Zn) content in wheat and its processed foods is an effective way to solve human Zn deficiency, which can cause a variety of diseases. This article summarizes the works on Zn in wheat grain, wheat processing, and wheat-derived foods. Grain Zn content in wheat was 31.84 mg·kg However, at least 25% of the global population is at risk of Zn deficiency  zinc content in wheat, wheat processing, and wheat-derived foods and (2) the bioavailability of Zn in wheat.−1 to meet the Zn needs of the human body  The amount of Zn available in the soil in these areas is different. For example, the available Zn in the soil in China was 0.37 mg·kg−1, 0.53 mg·kg−1 in India, 0.55 mg·kg−1 in Pakistan, and 1.46 mg·kg−1 in Zambia  Grang wheat .−1, with an average value of 29.39 mg·kg−1  was added to the soil.In general, the average grain Zn content in wheat without Zn fertilizer was 28.96 mg·kgfication . Interes mg·kg−1  when 50 Therefore, the most effective way to increase grain Zn content in wheat may be combining soil fertilization and foliar fertilization or directly applying foliar fertilization. However, local environment and wheat varieties should also be considered when choosing a suitable fertilization method to increase grain Zn content in wheat.−1 in flour with an average value of 12.58 mg·kg−1  and three “reduced” (R) milling parts] and two kinds of bran parts . The flour collected by B1, R1, B2, R2, B3, and R3 is standard flour; that by B1, R1, B2, and B3 is bread flour; and that by B1 and R1 is refined flour . The pow quality .−1, which exceeds the fortification standard of 10.00 mg·kg−1 when flour extraction rate was 65–75%  > fried food (10.60 mg·kg−1) > cooking food (8.03 mg·kg−1). Baked foods have a remarkably higher Zn content than cooking foods and fried foods. This difference in Zn content may be ascribed to the following: (1) The Zn content of the flour used in these foods was different and ranged from 3.73 to 36.53 mg·kg−1. For example, the Zn content of unfortified flour was 10.51 mg·kg−1, whereas that of Zn-fortified flour and whole wheat flour was 14.82 and 26.79 mg·kg−1, respectively  when the peeling rate was 10% and had the lowest value (13.86) when the peeling rate was 0  treatment.Grain Zn content in wheat worldwide is 31.84 mg·kgrtilizer . Grain Z−1, respectively. The change rule of Zn content in different components of wheat is bran > shorts > flour; the change rule of Zn content in each powder path is bran > B flour > M flour, B3 > B1 > B2, and M3 > M2 > M1. However, only a few studies have been conducted in this area. Moreover, Zn content in different wheat-derived foods is remarkably different, for example, 13.65 mg·kg−1 in baked food, 10.65 mg·kg−1 in fried food, and 8.03 mg·kg−1 in cooking food. This difference in Zn content may be due to the method of food processing.Wheat milling has remarkable effects on Zn content. For example, Zn contents in flour, shorts, and bran were 12.58, 70.49, and 86.45 mg·kgZinc deficiency is a comprehensive problem. Rotation and other cultivation methods may be used to increase Zn content to a certain extent. For example, the rotation of corn and wheat results in a higher Zn content in the second quarter compared with that in the first quarter . AlthougDeveloping wheat varieties with grains that are rich in Zn is a new approach. Conventional wheat breeding and modern biotechnology methods , such asIn the future, we should focus on how to preserve Zn as much as possible during milling, such as the effects of wheat grain pre-treatment and milling procedures on flour Zn content. Moreover, we should also explore the impact of food processing methods on Zn content.Phytic acid is an important indicator that affects the effectiveness of Zn. Current research has focused on phytic acid content in wheat grains and flour. However, research on phytic acid content in wheat-derived foods is scarce. Next, we should strengthen the study of the effects of different processing methods on phytic acid content and Zn bioavailability.Zinc deficiency is a worldwide problem. Zinc fortification should strengthen international cooperation through international schemes, such as Harvest Plus. Moreover, we should raise public awareness of the dangers of Zn deficiency and obtain as much support as possible, such as sustained funding, from the local government.Therefore, suitable Zn fortification, appropriate processing, reasonable food type, international collaboration, and government support are important to meet people's Zn requirements through wheat.MW collected and analyzed the data. MW and XZ wrote this paper. XZ, FK, RL, and QF conceived and modified this paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


P < .05). In carcinoid tumor NOS, significant differences in CSS were found with increasing combined 8th AJCC stages (P < .001), except for that between stage II and stage III . While combined 8th TNM stage in NEC and OTC exhibited greater separations in CSS despite on‐going overlaps between groups. For carcinoid tumor NOS, stage II , and stage III  conferred no significant difference in CSS compared with stage I, while stage IV had an increasing HR of 5.09 (95% CI: 1.08‐24.08). Although combined 8th AJCC stage had a good ability to distinguish 10‐year CSS of patients with NEC or OCT, detailed 8th AJCC stage did not seem to be applicable. Detailed 8th AJCC categories of advanced stages in all the three groups conferred increased HRs with overlapping CIs. However, in the early and middle status, HRs did not increase with the increase of stages, or there was no difference in HRs between adjacent stages. Combined 8th TNM stage was not practical for judging the survival outcomes of colorectal carcinoid tumor NOS, especially in patients with stages II and III, but it provided useful prognostic information for NEC and OCT. However, for all carcinoid tumors, the prognostic values of detailed 8th AJCC stage were not enough accurate in the clinic. More optimized staging methods should be developed and validated in the future.The aim of our study was to explore the value of the 8th edition TNM staging system on evaluating the prognosis of colorectal carcinoid. Colorectal carcinoid patients between 1988 and 2015 were selected in the Surveillance, Epidemiology, and End Results Program (SEER) database for analysis. About 4286 patients with colorectal carcinoid tumors were identified, of which were carcinoid tumor NOS (n = 1726), neuroendocrine carcinoma (NEC) (n = 1346) and other carcinoid tumor (OCT) (n = 591). Worsening 10‐year CSS rates with increasing N status, M status, and SEER historic stage were demonstrated across all three above groups (all  For all carcinoid tumors, detailed 8th AJCC categories of advanced stages conferred increased HRs with overlapping CIs. However, in the early and middle status, HRs did not increase with the increase of stages, or there was no difference in HRs between adjacent stages. More optimized staging methods should be developed and validated in the future. In our cohort, population‐based data from a national cancer registry were selected to evaluate the value of the 8th AJCC staging system on the prognosis of colorectal carcinoid.22.1B+C. Although invasive depth (Tx) or positive lymph node metastasis (Nx) was unknown, some tumors had been confirmed to show distant metastasis (M1). Thus, these data were still included in the study, staging as stage IV , according to the actual status of tumor metastasis.A retrospective cohort study from 1998 to 2015 was conducted to select patients, diagnosed with colorectal carcinoid tumor, whose age more than 18 years in the Surveillance, Epidemiology, and End Results (SEER) database. This version of the SEER database we used had been released April 2018 (November 2016 submission). Cases were stratified by histopathological type as follows: carcinoid tumor NOS (8240/3), NEC (8241/3), and OCT . Tumor sites were limited to colon (C18.0‐18.9) and rectum (C19.9 and C20.9). The included subjects contained a single primary malignancy and clear follow‐up information. Age, sex, race, tumor location, grade, histologic type, marital status, T status, N status, M status, and surgery information were assessed. TNM classification was restaged according to the 8th edition AJCC Cancer Staging Manual. Because in SEER data N1c  was missing, no analysis of the N1c subgroup was performed. Because no obvious distinctions of M1b (metastasis distributed in more than one organ) and M1c  were made, stages IVB and IVC were merged for analysis as stage IV2.2http://www.R‐project.org/). Two‐sided P value less than .05 was considered significant.In order to facilitate the statistical calculation, we combined goblet cell carcinoid, mixed adenoneuroendocrine carcinoma, adenocarcinoid tumor, enterochromaffin cell carcinoid, and atypical carcinoid tumor into other carcinoid tumors (OCT). The main outcome was death from colorectal carcinoid tumor. The cumulative incidence function (CIF) method, described by Pepe and Mori,33.1As shown in Table 3.2P < .001), except for differences in CSS between stages T1 and T2 (P = .594) and between stages T3 and T4a (P = .670) , except for that in CSS between N1a and N1b stages (P = .479). N0 stage had a CSS rate of 86.9% compared with that for N1a/N1b, N2a/N2b, and Nx . Also, M stage was an obvious indicator for CSS (P < .001). CSS declined steeply to 29.0% for M1, compared with M0 (87.4%). However, M1a had a similar 10‐year rate of CSS with M1b . Marked differences in CSS were showed with increasing SEER historic stage (P < .001), and combined 8th AJCC stages (P < .001) except for differences in CSS between stage II and stage III .Within carcinoid tumor NOS n = 1726), T stage was an important indicator for CSS  Figure . Stages P < .001), except for those between IIA and IIC , between IIA and IIIA , between IIB and IIIA , between IIB and IIIB , and between IIC and IIIC . The rates of 10‐year survival decreased to 53.6% and 40.1% for stages IVA and IVB+C, respectively, with no significant difference between them (P = .175). Besides, the rates of 10‐year survival were 99.6% and 92.1% for stages IA1 and IB, respectively (P = .005)  Table .3.3P < .001), combined 8th AJCC stage (P < .001), and increasing M status . Although, T stage was also an important indicator for CSS (P < .001) both in NEC and in OCT, again showing overlaps in CSS curves between T stages. The 10‐year CSS rate of T1 was less than that of T2 ; however, similar to than that of T3  and T4a  in NEC. Besides, there was no difference in the 10‐year CSS rate between T4a and T4b . In OCT, the rate of 10‐year survival of T1 was similar that of T2  and T3 . With the progression of the N stage from N0 to N2b, the 10‐year CSS rates decreased gradually both in NEC and in OCT. But in NEC, the 10‐year CSS rates of N1a, N1b, and N2a overlapped , while in OCT N1b and N2a overlapped (PN1b vs N2a = .125) (Table For both NEC n = 1346) and OCT (n = 1214), significant differences in CSS were found with increasing SEER historic stage  Table , Data S1P = .019) in OCT. Even there was no difference in the 10‐year CSS rates of several stages, such as IB, IIA, and IIIA  in NEC, and IIB, IIC, and IIIA  in OCT  showed no obvious difference in CSS compared with T1 stage, T1, T3, T4a, T4b, and Tx conferred HRs of 2.53 (95% CI: 1.68‐3.8), 2.80 (95% CI: 1.55‐5.05), 5.01 (95% CI: 3.02‐8.31), and 7.86 (95% CI: 5.11‐12.11), respectively, with overlaps between adjacent categories. All N categories had increasing HR values compared with N0 , except for N1a , with overlaps between adjacent stages. Compared with M0, M1a, and M1b conferred significant differences in CSS , showing overlaps between adjacent stages. Also compared with M0, M1 conferred a significant difference in CSS . The HR estimates of SEER regional and distant stages revealed a clearer pattern, showing HRs of 3.38 (95% CI: 1.64‐6.98) and 8.96 (95% CI: 3.21‐25.09), respectively, in comparison with localized. Stage IV had a significant pattern, conferring HRs of 5.09, compared with stage I, while stage II and stage III not  (Table CSS showed no obvious differences from the reference (stage IB) for stages IIA , IIB , IIIA  or IIIB , while stage IA revealed a smaller HR . In addition to those stages, HR estimates generally manifested an upward trend, with overlapping CIs , N status , M status (M1a and M1b). Compared with M0, M1 had significant differences in CSS of NEC  and OCT , respectively. For NEC, compared with T1, no obvious differences in CSS were showed for any T stage. For OCT, all T stages had increasing HRs compared with T4a , except for T2 and T3. Compared with the reference, combined AJCC stages showed an obvious impact on CSS, with stages III and IV having increasing HRs , except for stage II Table .B+C ). However, in the early and middle status of NEC and OCT, HRs did not increase with the increase of stages, or there was no difference in HRs in adjacent stages . Advanced detailed 8th AJCC categories in OCT showed increasing HRs with overlapping CIs , except for T1 in all three carcinoid tumors, with 10‐year CSS of 88.0%, 44.4%, and 85.4% in each group, respectively. Why was the survival rate of pT1 more abnormal? This might be associated with the inherent nature of carcinoid itself.The 8th edition AJCC staging system of colorectal cancer revised and added some of the details of regional lymph node (N) and distant metastasis (M) in anatomy, but had no update for T stages.P < .001) in carcinoid tumor NOS, except for that between stage II and stage III , while combined 8th TNM stage in NEC and OTC showed greater separations in CSS despite continuous overlaps between groups. Maggard et alWe also demonstrated that significant differences in CSS were found with increasing combined 8th AJCC stages (Although combined 8th AJCC stage had a good ability to distinguish the 10‐year CSS of patients with NEC and OCT, detailed 8th AJCC stage did not seem to be applicable. Detailed 8th AJCC categories of advanced stages in all the three groups conferred increased HRs with overlapping CIs. However, in the early and middle status, HRs did not increase with the increase of stages, or there was no difference in HRs between adjacent stages. Similar grading prognostic results for carcinoid could be seen in lung carcinoid.There were still some limitations and deficiencies in this study. First, although the included cases were mainly NEC and other poorly differentiated carcinoid types, partially well‐differentiated carcinoid tumors were still contained in the group of carcinoid tumor NOS, better staged according to the staging system of colorectal NET,Despite these limitations, our study provided valuable information on the long‐term survival outcome of colorectal carcinoid, especially when the updated staging system had not been validated. Conclusively, based on the findings in this study, we proposed that the combined 8th TNM stage was not practical for judging the survival outcomes of colorectal carcinoid tumor NOS, especially in patients with stages II and III, but it provided useful prognostic information for NEC and OCT. For all carcinoid tumors, detailed 8th AJCC categories of advanced stages conferred increased HRs with overlapping CIs. However, in the early and middle status, HRs did not increase with the increase of stages, or there was no difference in HRs between adjacent stages. More optimized staging methods should be developed and validated in the future.The authors declare that they have no competing interests.XXL and ZQH conceived and designed the study, XKZ and WXH performed the analyses, PQG, CHC, and ZW provided assistance in writing the manuscript and support in interpreting results. All authors discussed the results and implications of the analysis and commented on the manuscript at all stages.Data S1Click here for additional data file.Figure S1Click here for additional data file.Table S1‐S2Click here for additional data file.


The processing temperature at 1123 K and the treatment with HCl + H2O2 were key parameters influencing the purity, crystallinity, stability, and optical/electrical properties of bamboo-like morphology CNTs. Selected multiwalled CNTs (MWCNTs), from 1 to 20 wt%, were electropolymerized through in-situ polarization with conductive polymers (CPs), poly(aniline) (PANI) and poly(pyrrole) (PPy), for obtaining composites. In terms of structural stability and electrical properties, MWCNTs obtained by CVD were found to be better than commercial ones for producing CPs composites. The CNTs addition in both polymeric matrixes was of 6.5 wt%. In both systems, crystallinity degree, related to the alignment of PC chains on MWCNTs surface, was improved. Electrical conductivity, in terms of the carrier density and mobility, was adequately enhanced with CVD CNTs, which were even better than the evaluated commercial CNTs. The findings of this study demonstrate that synergistic effects among the hydrogen bonds, stability, and conductivity are better in PANI/MWCNTs than in PPy/MWCNTs composites, which open a promissory route to prepare materials for different technological applications.In this work, the optimal conditions of synthesizing and purifying carbon nanotubes (CNTs) from ferrocene were selected at the first stage, where decomposition time, argon fluxes, precursor amounts, decomposition temperature (at 1023 K and 1123 K), and purification process (HNO Conductive polymers (CPs) and conductive polymer composites (CPCs) are promising semiconductor materials for a wide variety of applications because of their tunable physical/chemical properties, mechanical flexibility, low weight, reversible doping, adequate bio-compatibility, and large-scale production . Differe−1 has been reported as a function of CNTs content [−1 [Additionally, PANI and PPy nanocomposites with different embedded nanostructures combined the synergistic effect of each one to obtain singular properties. These conjugated polymers are reinforced with either carbon nanotubes (CNTs), reduced graphene oxide powders, or metallic or ceramic nanoparticles, promoting the overall electrical conductivity in a wide variety of applications ,23,24,25 content ; whereastent [−1 ,29. Thustent [−1 . Among ttent [−1 . Recent tent [−1 ,33; althtent [−1 ,35,36,37tent [−1 ,39,40. FIn this paper, a systematic study is reported to evaluate the different parameters that influence the stability and electrical conductivity of CPs (PPy or PANI)/MWCNTs nanocomposite films to be potentially used as sensors or thermoelectric devices. During the first set of experiments, it was realized the synthesis of MWCNTs by thermal chemical vapor decomposition (CVD) at different experimental conditions. These samples were acid functionalized and characterized to select the optimal conditions to produce nanocomposites, from high purity MWCNTs and conjugated polymers, i.e., PPy or PANI, using polymerization assisted through in-situ polarization technique (potentiostatic method). The synergistic electronic interaction has been analyzed as a function of different amounts of MWCNTs (0–20 wt%) in both CPs. A special focus has been placed on the structure, stability, and electrical conductivity of the CPs (PPy or PANI)/MWCNTs nanocomposites.10H10Fe, Sigma-Aldrich, Mexico City, Mexico, 98%) as single source precursor and catalyst. The CVD experimental setup consisted of a three-zone horizontal furnace  with a tubular quartz reactor (120 cm in length and 5 cm in diameter), under argon  atmosphere. The initial weight of C10H10Fe (W) was of 0.1 and 0.2 g, which were placed into the equipment using a precursor temperature (Tprec) of 473 K, temperature previously obtained from thermogravimetric analysis, whereas the vapors were transported into the hot zone at two decomposition temperatures (T) of 1023 and 1123 K, and two decomposition times (t) of 30 and 60 min.MWCNTs powders were obtained by a hot-wall CVD process at atmospheric pressure, using ferrocene . Then, 60 mg of powders was added into the purified solution and it was maintained under stirring at 348 K for 4 h under reflux conditions. Thereafter, dispersion was neutralized with deionized water and ethanol, subsequently centrifuged at 2000 rpm during 5 min, and filtered and dried at 373 K for 24 h.Purification of CNTs powders fabricated at different experimental conditions was done with an acid solution composed by 20 mL of 3 M hydrochloric acid  + 20 mL of a solution 30 vol.% of hydrogen peroxide  + 20 mL of sulfuric acid 30 vol.%  was prepared. Subsequently, 60 mg of obtained sample was processed using a similar procedure.To observe the influence of the chemical attack on the CNT structure, samples synthesized at 1123 K were purified with a different procedure. A mixture of 20 mL of nitric acid 3 M (HNO−1 by 4-point probe method) were also purified by both methods and characterized for comparison.Additionally, commercial multi-walled CNTs, , lithium perchlorate  and pyrrole , respectively. In the case of poly(aniline), HCl, ammonium persulfate ((NH4)2S2O8, Sigma-Aldrich, Mexico City, Mexico, ≥98%) and aniline  were used. Based on previous reports, the following procedure was realized [Two conducting polymers were synthesized using a potentiostatic method. Electrolytic and oxidant agents as well as the monomer used to synthesize poly(pyrrole) were oxalic acid ; thereafter, 50 mL of this solution was mixed with 50 mL of a pyrrole solution (0.3 M) and sonicated for 30 min. Then, 200 mL of this dispersion as placed into the cell compartment, in which the 316L stainless steel and AISI 1018 carbon steel were working and counter electrodes, respectively. The nanocomposites were obtained in situ by applying a constant potential of −1100 mVEocp vs. SCE for 30 min and then kept under mechanical stirring again for 30 min.Different amounts of MWCNTs  were prepared with a solution of 0.1 M oxalic acid + 0.1 M LiClOEocp was applied vs. SCE for 30 min, but in this case, to assurance emeraldine formation, a solution of 0.1 M HCl + 0.1 M (NH4)2S2O8 in a 1:1 ratio (v/v) was prepared. This solution was added into 0.3 M of aniline following the same procedure with the exception that the system in the electrolytic cell was kept at 383 K in a cooling bath while using the 316L stainless steel as working and counter electrodes. A power supply (BK Precision 1746B) was used in the potentiostatic experiments.For PANI nanocomposite films, a potential of −600 mVα radiation (λ = 0.15405 nm). The equipment was operated at 35 kV and 25 mA in a θ-2θ configuration. The evaluated range was from 2θ = 20° to 70° at a speed of 0.02° min−1.To verify the structure and purity of MWCNTs, X-ray-diffraction (XRD) patterns were realized in a D8 Advance, Bruker diffractometer with a Cu K−1); previously the samples in powders form were dispersed into deionized water, using a Cary 5000 UV-vis-NIR spectrometer (Agilent Technologies) in the 200–1000 nm range with a scan rate of 600 nm min−1.Ultraviolet-visible (UV-vis) and Raman spectroscopies were also used to study the molecular structures of pure compounds (MWCNTs and CPs), as well as the interfacial structure between both components forming the composites . UV-vis −1 shift at spatial resolution of 2 cm−1. The scanning parameters for the spectra were: 10 s of acquisition, an objective of 100×, and a numerical aperture of 0.85. Five scans were acquired for each experiment to assurance and adequate signal to noise ratio.Raman studies were realized in a Renishaw InVia microscope using an excitation source of 514 nm and a laser power of 20 mW. The samples were scanned from 500–3000 cm−1 to 450 cm−1 using a Perkin–Elmer Spectrum One 51,394 series spectrometer equipped with an attenuated total reflectance accessory (ATR). Thermogravimetric analysis was realized in a Labsys Evo, Setaram TGA/DSC equipment. Then, 10 mg of each sample was placed in alumina crucibles and heated from 298 K to 1123 K using a heating rate of 10 K min−1 under argon atmosphere (flow rate: 20 mL min−1). Samples were maintained for 5 min at 1123 K and then cooled up to room temperature.Fourier transform infrared (FT-IR) was collected in the range from 4000 cmThe morphological aspects of the MWCNTs and composites were analyzed by scanning electron microscopy using a JEOL JSM-6701F microscope at a 5 kV acceleration voltage. Samples were sputter coated with Au-Pd for 30 s on a Quorum Q150T ES sputter coater system. Electrical measurements of both kinds of nanocomposites were performed by a conventional 4-point collinear probe using a Keithley Model 2410C instrument. The analysis was realized using a software based on the proportional integral-derivative approach (PID). For these measurements, composite powders obtained were compressed at 528 MPa to get pellets (10 mm in diameter and 1.7 mm in thickness) followed by a sintering process at 373 K for 4 h. Reported electrical conductivity values were the average of three samples for each condition. The Hall Effect measurements were realized using van der Pauw configuration at room temperature using an ECOPIA HMS 3000 apparatus.4, C2H2, EtOH, or CO is expensive because of the complex purification process [The synthesis of CNTs using hydrocarbon sources as CH process , whereas process . Among d process . For exa process .Then, du process , but oth3C in the structural BCC phase (PDF 00-003-0400). MWCNTs pattern shows weak reflections at 26.10° (002), 42.80° (100), and 45.80° (101), according to the PDF 00-002-0456 chart. As expected, the purification of MWCNTs reduces the signals of the Fe and Fe3C structural phases  with and without purification is shown in the l phases b. In fac3C phase formation. The acid treatment with HCl almost removed the amorphous carbon structures and iron reflections; a small deviation of the (002) peak of the purified samples can be related with an increase in the carbon inter-layer spacing [3C phase were purified with a different chemical treatment (HNO3 + H2SO4) to observe changes in the crystallinity degree. XRD pattern of purified sample with this solution is shown in 2O2 solution, the signals of iron impurities almost disappeared.For all the samples, the XRD patterns were very similar, but an increase of 373 K was enough to eliminate the Fe spacing . The eff spacing ,50, even spacing . Differe spacing . The CNTt is crystallite size, λ = CuKα wavelength (0.15405 nm), β = FWHM , and θ = Bragg angle. Additionally, the crystallinity degree of MWCNTs was calculated from a two-phase model (Equation (1)) in combination with a deconvolution process (pseudo-Voigt peak function) [To analyze possible changes in the crystallite size, an estimation of overall samples was realized from typical Scherrer equation unction) .(1)Wc,xi, j, are the numbers of crystalline diffraction peaks from MWCNTs and amorphous scattering peaks from amorphous carbon, respectively. In this equation, , ki = 1 .2O2, i.e., the chemical attack in the carbon structures is more severe in the produced MWCNTs using an oxidation with a HNO3 + H2SO4 solution. It has been reported that an oxidation of CNTs with HNO3 solution is more efficient in reducing the amorphous carbon phase as well as metal impurities in the CNTs than other oxidants; however, it can also affect the attack of the carbon structure breaking the CNTs into shorter segments [2O2 were used for further characterization and used to produce MWCNTs/polymer composites.The comparison of both chemical treatments indicated that crystallite size is reduced during the purification process. On the other hand, the percent crystallinity is higher in samples treated with HCl + Hsegments ,55. Furtsegments . The abo−1, –OH bands among 3300 and 3700 cm−1, and asymmetric and symmetric stretching of CHx groups are observed between 2900–2800 cm−1. The band in the wavenumber of 2330 cm−1 is associated with the CO2 from the air. The stretching of C≡C bonds is slightly observed at 2140 cm−1, whereas that of C=C bonds is at 1560 cm−1. The peak at 1660cm−1 is correlated with the C=O stretching presence of the carboxylic acid group (–COOH). Vibrational modes associated with MWCNTs are observed at 1445 and 1575 cm−1, C–C bands must be located at 1377, and C–O bonds of the carboxyl group are obtained at 1010 cm−1 [FT-IR was also used to examine the MWCNTs functionalization and to compare it with commercial MWCNTs under similar purification process a,b. From010 cm−1 ,59,60.−1 and C–H stretching bands at 3180 and 2800 cm−1 [2 trapped into the MWCNTs was observed at 2330 cm−1 [−1 [−1; and rocking and deformation out of plane vibrations of CH2 or CH3 groups at 1467 cm−1. Similarly, 1414 and 800 cm−1 are the stretching of C–N groups. The bands at 1228 cm−1, 1110 cm−1, and 1020 cm−1 correspond to the C–O stretching/OH bending vibrations and/or the stretching of C–O in ester, ether, and phenol of carboxyl, respectively [2 or CH3 groups only appear in commercial samples, and (iii) there is C–O shifting due to the chemical environment in the synthesized CNTs. In all synthesized CNTs, there is the presence of two bands at 605, 757, and 655 cm−1 that arise after purification with HCl and H2O2. Because the synthesized MWCNTs can present some structural imperfections, there are some carbonaceous materials  that might contribute to the appearance of these bands [−1), attributed uniquely to MWCNTs, leads to a better interpretation of FT-IR results [On the other hand, commercial MWCNTs showed the typical O–H bands in the region from 3300 to 3700 cm800 cm−1 ,62, resp330 cm−1 ,64. The cm−1 [−1 ; C=C bonectively ,67. The se bands . The ide results ,69. ThenThe structural dispersion and stability of CNTs have been correlated with the absorption intensity. That is, better dispersion-stability, greater absorption intensity, and minimum changes in the spectrum should appear ,71,72. F2O2. The UV-vis of commercial carbon nanotubes is presented as π-plasmon resonance [esonance . With reesonance . In agreesonance .π-plasmon absorption [π-band electrons (common band feature in CNTs at ~175–245 nm) [0.1F50t60, W0.2F50t30, W0.2F50t60 (202 nm) and W0.1F50t30, W0.1F100t60, and W0.2F100t30 (224 nm); these bands appear by the π-plasmon resonance, common in CNTs [Commercial CNTs typically show the characteristic band at 272 nm, attributed to the sorption , and the–245 nm) ,81. In t in CNTs ,81. No c0.1F50t60 and purified with acid chemical treatment (HCl + H2O2) was analyzed by Raman spectroscopy , 1581(G), and 2641(G′) cm−1 [−1 is observed (D′). This band was narrower than in not purified CNTs, and it is evidence of an adequate purification process. D′ is also related to the lattice vibration of defective graphite-like materials [1g symmetrical stretching coming from disorder and defects present in CNTs [G’/IG ratio also confirms that the structural defects are higher in the as-obtained sample (0.55) in comparison with commercial CNTs (0.21). The ID/IG ratio has been widely used to evaluate the structure’s order; thus, a value near zero is desirable [D/IG and IG’/IG ratios were obtained using the maximum heights of the D, G, and G’ bands after subtracting a baseline. As-prepared CNTs (W0.1F50t60) show an ID/IG ratio of 0.81 versus 2.11 for commercial CNTs. These results indicate that commercial CNTs display less order structures than the selected sample.Another important feature to analyze in the MWCNTs is evaluated structural changes after purification; for this reason, a selected sample synthesized with the following parameters Wtroscopy a. In thitroscopy b. This tG′) cm−1 . Additioaterials ,85. In t in CNTs ; the G b in CNTs . The amo in CNTs . Meanwhiesirable . The ID/TEM micrographs and selected area electron diffraction (SAED) patterns were used to confirm structure and morphological features before and after purification a–f; the The coiled tubes present “elbow-like junctions”, making it difficult to measure the diameter, but the walls of these CNTs are thick ,92,93. AEocp vs. SCE and PANI of −600 mVEocp vs. SCE both for 30 min of deposition time.Electropolymerization of samples was carried out using a potentiostatic method in two different solutions to obtain PPy/MWCNTs and PANI/MWCNTs film composites. Different amounts of the synthesized and commercial MWCNTs powders were added in the electrolyte at 1, 5, 6.5, 8, 10, and 20 wt% on the growth film to evaluate the effect on the electrical properties. Additionally, diverse overpotentials were analyzed until they reached an adequate potential for PPy of −1100 mV−1 correlated to the -NH stretching vibration mode of PPy [−1. C–N stretching and N–H ring in-plane bending are located between 1325 and1396 cm−1. Typical C-C stretching in-ring and C–N stretching are found at 1266 cm−1. Additionally, the C=C–N of ring in-plane deformation, C–N stretching, and N–H ring in-plane bending are at 1125 and 944 cm−1, respectively. A combination of C=C–N ring in-plane deformation, C–C=C inter-ring in-plane bending; C–C in-ring stretch, and C–C–N inter-ring in-plane bending, can be located at 1085 cm−1. Bands in the wavenumber range from 800 to 805 cm−1 correspond to N-H ring out-of-plane and C–H ring out-of-plane bending. The bands at 730 cm−1 show the C-H ring out-of-plane bending, whereas –CH flexion of cyclic plane can be observed at 633 cm−1 [−1 that are overlapped with the –NH band. Additionally, the stretching vibrations of CHx groups appear in the wavenumber range of 2900–2800 cm−1. Finally, the vibrational modes associated uniquely to MWCNTs appear at 1445 and 1575 cm−1 [The chemical interaction of the films was initially studied by FT-IR measurements a–d. Puree of PPy ,98; C–N–633 cm−1 ,99. Some575 cm−1 ,69. It i−1, C–H bending of benzenoid ring at 2890 cm−1, C=C vibrations of quinoid units, quinoid ring-stretching at 1500 cm−1, bending of CH in CH2 at 1452 cm−1, N–H bending mode at 1400 cm−1, CN stretching in benzene and quinoid rings at 1305 cm−1, CH bending at 1250 cm−1 and 1000 cm−1, C–H in-the-plane at 1130 cm−1, electronic transition of electrons in PANI structure at 1100 cm−1, C–H in-plane bending at 1000 cm−1, and the CH deformation of 1,4-disubstituted ring/Q ring at 826 cm−1 [On the other hand, the FT-IR spectrum of pure PANI displays the following bands: NH stretching vibration of secondary amine overlapped with the free and hydrogen bonded NH at 3440 cm826 cm−1 ,102,103.The spectra of electrodeposited PANI/MWCNTs showed an increase in the intensity in the bands of the functional groups that they have in common; one example is the overlap of OH in carboxylic groups adhered to the surface of CNTs as well as the NH stretching in the CN bands. The presence of some low intensity bands when MWCNTs are added in 5 wt% and 20 wt% into the polymer matrix matched with the unbounding hydroxyl groups. Based on this evidence, it is clear that the MWCNTs also could be interacting electrostatically with the PANI through the same interactions as PPy, i.e., NH…O=C–R and R–NH…H–O–R and π-π interactions see . The FT-−1 that corresponds to the C=C bonds and the inter-ring C–C mode of polaron structure, which evolves from the overlapping of neutral, oxidized (polaronic), and fully oxidized (bipolaronic) species located at 1560, 1580, and 1610 cm−1 [In order to complement the FT-IR studies and evaluate the effect of electropolymerizing the PPy and PANI in presence of different wt% of MWCNTs, as well as to analyze the disorder and defects in crystal structure, Raman spectra were evaluated and presented in 610 cm−1 .2O2 are shown in The Raman spectra of the electropolymerized PPy composites with different compositions of MWCNTs synthesized at 1123 K and purified with HCl + H−1 (G), 1574 cm−1 (D), 1608 cm−1 (D’), and 2649 c−1 (G’) seem to correspond to MWCNTs, although some overlapping in the D and G bands of PPy cannot be discarded. An increase in the intensity of Raman bands with the amount of MWCNTs is observed. The ID/IG ratio for polymer composites was computed from intensities, and the results are shown in D/IG ratio is very useful to analyze the extent of defects, and it has also been reported to be sensitive to molecular interaction at the interface [Raman spectra show that the bands more prominent at 1326 cmnterface .D/IG is closed to zero, it indicates a better structural order; specifically, in this case, it suggests a better molecular interaction between PPy-MWCNTs. ID/IG ratio is quite different in the samples with the commercial CNTs, where a great quantity of disorder is obtained, since this ratio varies from 1.44 to 1.67; however, the composites still display a low quantity of defects (IG’/IG), D/IG can be related to a diameter of commercial of CNTs and poor interaction with PPy during electropolymerization process. Then, the behavior of ID/IG ratio suggests that a better interaction occurs with the as-prepared samples with an adequate electrostatic interaction with amounts above 6.5 wt%.The PPy/MWCNTs composites display a slight increase in this ratio when the samples are electropolymerized with low amounts of carbonaceous structures, 1 wt% (0.953) and 5 wt% (0.903), whereas with higher addition from 6.5 (0.745) to 20 wt%, this ratio decreases until 0.692. It is well known that when I−1 corresponding to the stretching vibrational modes of the charged nitrogen segments, i.e., the C–N+. stretching vibrations of delocalized polaronic structures, and the second at 1570 cm−1, corresponding to the C–C- stretching of B and Q and C=N [D/IG ratio in PÄNI composites is low, with a small percentage of MWCNTs, and it increased from 6.5 wt%. The general tendency in the case of composites with commercial CNTs is a reduction in the ID/IG ratio  and Thakur et al. (ID/IG = 1.14) [On the other hand, PANI spectra showed two main contributions, the first at 1350 cm and C=N , Figure IG ratio . Most ofo et al. , (ID/IG= = 1.14) , for PAN = 1.14) .The ultraviolet-visible spectra of electropolymerized samples were analyzed to evaluate the electron states of the pure PPy and PANI polymers, as well as to corroborate the interfacial interaction in the composites with MWCNTs. Two main peaks were observed in the wavelength intervals of 200–350 nm and 800–1100 nm. The first peak ca. 260–270 nm is recognized to the polaron state coming from PPy and MWCNTs . The polOn the other hand, The most important difference to highlight is that the polaron-π* transition tends to disappear after nanocomposite electropolymerizing, which is related to the interaction through the MWCNTs carbonyl groups. Similar absorbance spectra were obtained at any composition, when commercial MWCNTs were used to obtain composites; however, in all the spectra, the π-polaron transition is missing. Thus, by comparing the UV-vis spectra PANI nanocomposites using both MWCNTs types, it was observed that samples with high absorbance are those fabricated with an amount of 6.5 and 20 wt%; whereas for commercial CNTs, the samples that display the maximum absorbance values were with 5.0 and 6.5 wt%. In addition, the signal that corresponds to polaron-π* transitions within doped quinoid (Q) structure remains with nanocomposites prepared with CVD CNTs, but it disappears with commercial ones, highlighting a better interaction of the composites with the method used in this study. It is also important to recall that under these conditions, the conductive phase of PANI remains unaltered in the UV region after electropolymerization process . Recent Finally, during the acid functionalization of MWCNTs, different -OH and -COOH groups are attached at the open ends and defect sites , and suc−2 ± 8.49 × 10−2 S cm−1, whereas the base-PPy nanocomposites tended to increase the electrical measurements with the amount of CNTs (−1), followed by 10 wt% (5.5 × 10−1 ± 1.15 × 10−2 S cm−1) and 20 wt% (5.0 × 10−1 ± 0.0 S cm−1). The other samples showed an uncertain contribution of the CNTs to the improvement of electrical conductivity.A four-point probe method was used to determine the electrical resistance and conductivity (δ) of pure PPy, PANI, and composites in pellet shape, at room temperature. Pure PPy showed an electrical conductivity of 1.16 × 10 of CNTs . However−2 ± 8.80 × 10−4 S cm−1 whilst, in the case of PANI nanocomposites, the electrical conductivity presented a gradual enhance with the carbonaceous structures quantity. In this case, high conductivities were observed for samples with 20 wt% of CNTs (2.5 ± 0.0 S cm−1). The increase in the electrical conductivity of both polymers nanocomposites is commonly attributable to the π-π stacking between PPy or PANI and CNTs providing easier conductive channels. The differences between both polymers are due to the number of functional groups that lead to electrons transfer in a more efficient way between carbon atoms [On the other hand, pure PANI showed values 1.10 × 10on atoms , which ion atoms ,118, but−4 ± 8.49 × 10−4 S cm−1 to 1.33 × 10−2 ± 2.1 × 10−4 S cm−1 with 1 and 2 mA, respectively. Thereafter, the electrical conductivity reduces using a current of 5 mA (1.31 × 10−2 ± 1.23 × 10−3 S cm−1), which can be due to the structural changes during the applied current.To observe the changes in the electrical behavior with the applied current, nanocomposites with an amount of 6.5 wt% were evaluated by the four-point probe method using 1, 2, and 5 mA, −1. The result indicates that an adequate synergy with electrical stability has been reached between the MWCNTs and PPy [−2 ± 8.80 × 10−4 to 9.9 × 10−3 ± 3.18 × 10−4 S cm−1; the lowest value is observed at 5 mA. It is possible that the emeraldine phase of PANI changes its oxidizing degree, and then it reduces the electrical conductivity. On the other hand, PANI composites again showed a slight increase with the electrical conductivity from 3.24 × 10−2 ± 6.48 × 10−4 to 5.06 × 10−2 ± 2.15 × 10−4 S cm−1 by varying the applied current from 1 to 2, but again they were reduced up to 2.94×10−2 ± 7.71 × 10−4 S cm−1 with 5 mA. These results clearly indicate that after this applied current, the composite loses its electrical stability.The analyzed PPy/MWCNTs nanocomposites with 6.5 wt% present a fairly constant conductivity between 12.5 ± 1.90 and 12.53 ± 1.23 S cm and PPy ,120. Ele−3 S cm−1) [σ values of the PPy/MWCNTs and PANI/MWCNTs are low compared to previous reports in the literature, which display values in the range of 40–60 S cm−1 for PPy composites [−1 for PANI composites depending of the CNT amount [In comparison with other composites such as PPy/perovskite manganite (5.0 × 10 S cm−1) , it can mposites ,122 and T amount , but it T amount .−1 [−1 [−1 [−1 when PPy is prepared with a surfactant [4)2S2O8), as oxidant, has been reported to be 0.143 S cm−1 [It has been reported that the conductivity in CPs varies with their morphologies and synthesis methods. The morphology observed in this work is presented as inset figures a,b. Diff−1 , whereas−1 [−1 ; PPy, pr [−1 [−1  and fromrfactant . Similar3 S cm−1 .n) and mobility (μ) at 300 K, using a Hall field of 0.550 T orthogonal to the current density. The relevance of Hall effect measurements is described in the literature [n = 6.4 × 1016 ± 5.8×1014 cm-3, and μ = 1.9 ± 0.1 cm2 (V s)−1; in the case of pure PANI, n = 2.9 × 1017 ± 2.4 × 1014 cm−3 and μ = 17.9 ± 0.3 cm2 (V s)−1. Polymer nanocomposites with PPy displayed values of n = −1.6 × 1019 ± 1.6 × 1017 cm−3 and μ = 1.6 × 10−2 ± 1.3 × 10−4 cm−3 cm2 (V s)−1, whereas n = 4.9 × 1018 ± 6.1 × 1016 cm−3 and μ = 1.6 × 10−2 2.1 × 10−4 cm2 (V s)−1 were obtained for PANI composites. Conventionally, the positive carriers are “holes”, and the negative carriers are electron in a semiconductor material . Then, it can be observed that pure PPy presents an acceptor character, which is modified to donator character after adding the MWCNTs. In the case of pure PANI and PANI composites, both samples show an acceptor character [Hall effect measurements were also realized in these samples to determine the carrier density  and after electrical characterization, XRD measurements were realized using synthesized and commercial MWCNTs. The comparison with pure polymer matrixes is also presented in the spectra. XRD patterns of pure PPy display broad signals, which are typical of amorphous phases ,130, Figanotubes .Pure PANI patterns display the characteristic signal of the (200) basal plane of the orthorhombic structure at 25.5°; the amplitude is indicative of the amorphous nature in this polymer b. Other After the conjugated electron loss of pyrrole, polarons are linked together to form bipolaron during PPy polymerization . 12. As PPy/MWCNTs composites  display On the other hand, the TGA for PANI/MWCNTs  compositFrom the above results, it was found that the optimal conditions for synthesizing CVD CNTs modulate the stability, structural properties, and electrical features, which are essential for technological applications such as thermoelectric devices.3 + H2SO4 or HCl + H2O2) were also optimized and compared with commercial CNTs.In this work PPy/MWCNTs and PANI/MWCNTs composites were synthesized by electropolymerization process to determine changes in their stability and electrical properties. The conditions during the synthesis of MWCNTs by CVD process such as the decomposition time, argon fluxes, amounts of precursor, temperature (at 1023 K and 1123 K), and the purification process , but with high defects compared to commercial CNTs. PPy composites show similar electrostatic interactions, which are probably through hydrogen bonding, regardless of the MWCNTs amounts, but a better structural order was obtained from 6.5 wt%. In contrast, PANI/MWCNTs composites showed high structural order with low amounts of CNTs and increased after 6.5 wt%. The defects quantity (IG’/IG) of these samples is still higher than the observed in composites using commercial carbon nanotubes. The absorption bands of the PPy composites present the same transitions after polymerization process, whereas PANI/MWCNTs composites show that the polaron-π* transition is reduced after electropolymerizing. However, the conductive bands (polaron-π*) in the composites with commercial MWCNTs disappeared. Under these experimental conditions, an adequate amount to add them into the CPs matrixes was 6.5 wt%. The crystallinity of composites with optimized properties shows that the crystallinity degree and thermal stability related to the alignment of PANI and PPy chains on the MWCNTs are enhanced with the CNTs. Finally, in adequate amounts and synthesis parameters, the synthesized MWCNTs improve the carrier density and mobility of both CPs up to two orders in magnitude, which positively affect the electrical conductivity. Comparing both CPs, it can be concluded that the electrostatic interaction, stability, and conductivity are better in PPy/MWCNTs compared to PANI/MWCNTs composites.The results from structural and optical properties indicate that the main parameters influencing the purity of bamboo-like morphology CNTs are the processing temperature at 1123 K and the treatment with HCl + H