In this study, a method for compounding two semiconductor materials, In2S3 and Bi2S3, on the surface of g-C3N4via a one-step hydrothermal method is reported, and it was found that this resulting material showed remarkable properties. The advantages of this method are as follows: (1) the formation of a heterojunction, which accelerates the separation efficiency of photogenerated carriers; (2) a large number of holes and defects on the surface of g-C3N4 are conducive to the nucleation, crystallisation and growth of In2S3 and Bi2S3. Compared with its counterpart catalysts, the CN/In2S3/Bi2S3 composite catalyst has significantly improved performance. Due to its high degree of crystallinity, the adsorption capacity of the catalyst itself is also significantly improved. In addition, the stability of the composite material maintains 90.9% after four cycles of use, and the structure is not damaged. In summary, CN/Bi2S3/In2S3 composite materials are believed to have broad application potential in the treatment of dye wastewater.In recent years, photoelectrocatalysis has been one of the hotspots of research. Graphite-like carbon nitride (g-C 2S3/In2S3 composite.The proposed photocatalytic mechanism for the degradation of RhB on the surface of the 0.05CN/Bi Common methods that have been developed for dealing with organic pollution in water can be divided into three categories: physical, chemical and biological methods. Adsorption is the main physical method used,13 which mostly involves the use of activated carbon and diatomaceous earth as adsorbents. Other adsorbents have been also reported recently for wastewater treatment, e.g., sepiolite mineral nanofibers.14 However, the costs associated with this method are high and complete adsorption of the pollutants from water cannot be achieved. Oxidation reactions are the main chemical methods used in the remediation of water pollutants.15,16 Therefore, it is urgent to develop an environmentally friendly method to solve the current water pollution issues. As photocatalytic technology has the advantages of being green, highly efficient and causing no secondary pollution, it is one of the most promising methods for degrading pollutants in water that could be applied as a future strategy.17–19With the development of science and technology, the application of photoelectrocatalytic technology2),20 molybdenum sulfide (MoS2),21 Bi2S3,22 zinc oxide (ZnO),23 graphitic carbon nitride (g-C3N4).24 The unique forbidden band structures of semiconductors lead to the generation of electrons and holes (e− and h+) under the excitation of light of a certain wavelength. These e− and h+ then react with water molecules and oxygen in water to form strong oxidising substances, which oxidise and decompose the pollutants present in water into environmentally friendly molecules. Among these semiconductors, in 2009 g-C3N4 was first used by Wang et al. in the photocatalytic production of hydrogen. Due to the excellent photoelectric properties of g-C3N4, it has attracted the attention of many researchers in the field of photocatalysis.19,24 In addition to photocatalytic application,25 graphitic carbon nitride based materials are also promising for biomedical applications.26 However, some studies have shown that the rapid recombination of e− and h+ severely limits the photocatalytic performance of g-C3N4.27 To solve and overcome these difficulties, many researchers have made tremendous efforts,28,29 such as using different strategies to improve the catalytic performance of g-C3N4. For example, a higher number of active sites have been introduced in g-C3N4 by increasing its specific surface area,30 however, the coverage of dyes and other small molecules on the catalyst surface and in the pores makes the catalyst less stable. The latest research shows that a strategy of constructing heterojunction binary and multi-component catalysts not only accelerates the separation of e− and h+ but also expands the range of light response of these materials has attracted great attention.31–33 It has been reported in the literature that the construction of heterostructured catalysts leads to systems that have greatly improved photocatalytic performance.34–37 C. Auttaphon et al.38 synthesised a Z-scheme Bi2S3/ZnIn2S4 heterostructure for methylene blue degradation, which showed higher photocatalytic activity than the uncombined catalysts alone. Geioushy et al. used a one-pot method to prepare BiPO4/Bi2S3 for the reduction of harmful Cr(vi) driven by visible light.39 ABi2S3/Bi2W2O9 composite has also previously been prepared that shows 80% degradation of phenol after 120 min of irradiation, a performance that is substantially higher than those of pure Bi2S3 and Bi2W2O9 under visible-light illumination.40 An et al. synthesised a new Z-scheme In2S3/graphene heterojunction with a core–shell structure, which showed a methyl orange degradation rate of almost five times higher than that of pure In2S3 (ref. vi) under visible light. For degradation of rhodamine B (RhB), these photocatalysts have been reported recently.42,43 In summary, from the perspective of development, photocatalytic technology has great application prospects in the degradation of pollution and environmental protection.44,45At present, the reports on photocatalysts in the literature are mainly based on semiconductor materials, including titanium dioxide . In addition, by carrying out powder X-ray diffraction (XRD), photoluminescence (PL), X-ray photoelectron spectroscopy (XPS) and other characterisation methods, the composition of the catalyst in terms of its elemental content, its chemical valence state, morphology, and charge carrier transfer behaviour were carefully analysed, and the possible catalytic mechanism of the catalyst was explored and is discussed in detail. This work may provide a feasible practical example of a way of improving the photocatalytic performance of g-C3N4 through its combination with Bi2S3 and In2S3 in a heterogeneous composition as a reference for subsequent research.In this study, to verify the heterostructure photocatalyst theory, the ternary heterostructured photocatalyst g-C22.1Thiourea, absolute ethanol, RhB, urea, bismuth nitrate pentahydrate, indium nitrate, and other chemicals used in the experiments were of analytical purity (99%) and used without further purification. Deionised water was used throughout all of the experimental work in this study. All medicines come from Titan.2.22.2.1−1 to 550 °C, and held at this temperature for 4 h to obtain a yellow solid of g-C3N4, which was ground into a powder for subsequent use.An appropriate amount of urea was added to a crucible and closed the lid, and heated in a muffle furnace at a heating rate of 2.5 °C min2.2.23N4 powder was added to a 50 mL beaker, into which 20 mL of DMF  was poured and the reaction mixture was stirred at room temperature for 12 h to prepare a solution referred to as solution A.An appropriate amount of g-C2.2.33 solution with a concentration of 1 mol L−1 was added to a 100 mL beaker and stirred for ten min before adding 0.1 mmol of Bi (NO3) 5H2O, and stirring the resulting reaction mixture for 30 min. Then, to this mixture 0.1 mmol of In (NO3) xH2O was added and the mixture was stirred for 30 min. After this time 0.2 g of cetrimonium bromide (CTAB) was added and the reaction mixture was ultrasonicated for 30 min, to produce a solution referred to as solution B. The above solution A was slowly added dropwise to solution B to mix them together uniformly, then 0.6 g of thiourea was added and the reaction mixture was stirred for 30 min, before being poured into a 100 mL polytetrafluoroethylene liner and heated to 140 °C under hydrothermal reaction for 12 h. The resulting liquid was washed three times with ethanol and deionised water, and then dried in an oven overnight at 60 °C. g-C3N4/Bi2S3/In2S3 catalysts with different mass fractions of g-C3N4 were prepared, and the catalysts g-C3N4 and Bi2S3/In2S3 were prepared for comparison.70 mL of HON2.3−1. XPS measurements of the prepared samples were recorded using a PHI 5000 Versa Probe spectrometer, in which the binding energy positions were calibrated against the C–C bond peak that has a binding energy of 284.8 eV. The morphology characteristics of the samples were investigated using transmission electron microscopy  and scanning electron microscopy . UV-visible diffuse reflection spectroscopy (DRS) measurements were carried out using a UV-visible spectrophotometer (Shimadzu UV-3600) across a wavelength range of 200–800 nm, employing BaSO4 as a benchmark. Fluorescence emission and time-resolved fluorescence spectra were measured using a fluorescence spectrometer (Hitachi F-7000) over a wavelength range of 340–800 nm at an excitation wavelength of 320 nm, employing a 300 W xenon lamp (CEL-HXF300) as a light source.XRD patterns were recorded using a Bruker D8 Advance powder X-ray diffractometer equipped with a Cu-Kα radiation source. A Nicolet iS10 Fourier-transform infrared (FTIR) spectrometer was employed to record FTIR spectra of the samples in the wavenumber range of 500–4000 cm2.4where η is the photocatalytic efficiency; C0 is the concentration of the reactant before illumination and Ct is the concentration of the reactant after illumination for t hour.To determine the photocatalytic activity of the synthesised photocatalyst, the catalytic degradation of RhB was evaluated under simulated sunlight using a 500 W xenon lamp as a light source in a photoreactor . In a typical experiment, before being exposed to light the reactants and catalyst were placed in a quartz tube and magnetically stirred for 30 min in the dark to achieve adsorption–desorption equilibrium. At a given time interval after beginning the visible light irradiation, samples were taken from the reaction suspension (each with a volume of 5 mL), centrifuged at 8000 rpm for 10 minutes, and then the supernatant was removed. Then, the concentration of RhB in the sample solutions was analysed using a (UV-31/32/3300) UV-visible spectrometer (MAPADA) at its maximum absorption wavelength. To ensure the repeatability of the results, each run was repeated to obtain an average for each set of conditions. A blank test was also carried out by irradiating the reactant solution in the absence of the catalyst to evaluate its photo-induced self-sensitised photodegradation.33.13.1.12S3, CN, In2S3, Bi2S3/In2S3 and CN-xBi2S3/In2S3. The XRD pattern of pure CN shows two distinct diffraction peaks at 2θ = 12.43° and 27.54°, which can be indexed to the (002) and (100) diffraction planes, respectively, of g-C3N4 (JCPDS (87-1526)), attributed to its typical stacked aromatic rings and interlayer π–π stacking.46θ = 11.14°, 15.80°, 15.90°, 17.58°, 22.39°, 23.72°, 24.92°, 25.20°, 28.60°, 31.65°, 31.79°, 32.93°, corresponding to the (110), (020), (200), (120), (220), (101), (130), (310), (211), (040), (221), (301) diffraction planes respectively, of Bi2S3 (JCPDS No. 17-0320).22 The profile of In2S3 exhibits the characteristic diffraction peaks of β-In2S3 (JPCDS No. 65-0459).47 However, the XRD pattern of In2S3/Bi2S3 only shows the diffraction peaks of Bi2S3, showing that it contains little In2S3 content. In addition, one new weak characteristic peaks at 27.54° is present in the patterns of the CN/Bi2S3/In2S3 composites, which can be assigned to the (0 0 2) peak of g-C3N4. With an increase in the amount of g-C3N4 present in the catalyst samples, the diffraction peak of Bi2S3/In2S3 at 2θ = 24.92° went from being of high intensity to low intensity, reflecting the influence that it has on the phase crystallinity of Bi2S3/In2S3.As shown in 3.1.23N4 can be seen in CN-xBi2S3/In2S3, which is beneficial for the adsorption of dyes by the catalyst. 2S3, which is made up of a large number of hexagons with side lengths ranging from 0.3–1 μm. 2S3, which has a rod-shaped structure, where the rods have diameters in the range of 50–100 nm and a length in the range of 0.5–2.0 μm in size.In 2S3 and Bi2S3, the morphology of the composite of both materials in 2S3 surrounded by rod-shaped Bi2S3. This structure is more conducive to the transfer of photogenerated e− and h+ than the single catalysts alone. 2S3/In2S3, which shows the combination of flower-like In2S3 and a spherical Bi2S3 structure. Porous layered g-C3N4 has a large specific surface area and pores, so it provides more defects with which to facilitate the crystallisation, nucleation and growth of In2S3 and Bi2S3. In addition, the structures of In2S3 and Bi2S3 are not damaged. To analyse its structure in more depth, TEM and high-resolution TEM (HRTEM) were used to characterise 0.05CN/Bi2S3/In2S3. 3N4, from which it can be seen that the layered g-C3N4 of the film structure is consistent with the results presented in the literature. 2S3/In2S3, which is consistent with the image shown in 2S3 and the (4 0 0) crystal plane of In2S3. This result is consistent with the PXRD results.Compared with pure In3.1.32S3, Bi2S3, g-C3N4 and CN-xBi2S3/In2S3 were recorded and the results are presented in xBi2S3/In2S3 there is no obvious peak that is characteristic of Bi2S3.48 The peaks at 1327, 1417, 1559, and 1631 cm−1 in the same spectrum can be assigned as the characteristic absorption bands of g-C3N4, attributed to the vibration of the C6N7 skeleton and the typical stretching mode of the CN heterocycles.49To further demonstrate the surface properties and functional groups present in the samples, FTIR spectra of In−1 can be assigned to the breathing mode of the triazine units. In addition, the peaks at 772 and 1196 cm−1 are typical of In2S3 and the characteristic peak of Bi2S3/In2S3 is roughly consistent with In2S3.50,51 The characteristic absorption peak of g-C3N4/In2S3/Bi2S3 is consistent with that of g-C3N4, while the peak related to Bi2S3/In2S3 gradually decreases in intensity, which may be a result of the g-C3N4 peak being too intense.The peak at around 809 cm3.1.42S3/In2S3 heterojunction samples, 2S3/Bi2S3 exhibits the typical C 1s, S 2p, S 2s, N 1s, In 3d, and Bi 4f peaks expected for CN–Bi2S3/In2S3, Bi2S3/In2S3 and CN. The survey spectrum indicates that C and N exist on the surface of g C3N4, and Bi, In, and S on the surface of In2S3/Bi2S3. Besides this, as shown in 3N4 nanosheets, since the peaks at around 443.61, 157.43, and 225.01 eV can be assigned to the In 3d, Bi 4f and S 2s energy levels, respectively. The high-resolution C 1s, N 1s, In 3d, Bi 4f and S 2s XPS spectra of 0.05CN/Bi2S3/In2S3 are presented in  PBM data was replaced with SVG by xgml2pxml:<glyph-data id="z.dbd" format="PBM" resolution="300" x-size="8" y-size="10" xml:space="preserve">00000000000000000000000000000000111111110000000011111111000000000000000000000000</glyph-data><svg xmlns="http://www.w3.org/2000/svg" version="1.0" width="13.200000pt" height="16.000000pt" viewBox="0 0 13.200000 16.000000" preserveAspectRatio="xMidYMid meet"><metadata>Created by potrace 1.16, written by Peter Selinger 2001-2019</metadata><g transform="translate scale" fill="currentColor" stroke="none"><path d="M0 440 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z M0 280 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z"/></g></svg>N groups in the 0.05CN–Bi2S3/In2S3 heterostructure shifts lowers by 0.02 eV to 288.14 eV, which indicates that there are weak interactions between the Bi2S3/In2S3 and g-C3N4 nanosheets as a result of surface modification effects.52 The N 1s Gaussian curve in 2-hybridised nitrogen (C–NC), the N–(C)3 groups of the skeleton, and the surface uncondensed bridging N atoms with C–N–H functional groups attached.53,54 Compared to g-C3N4, the peak positions in the N 1s spectrum of 0.05CN/Bi2S3/In2S3 are shifted to higher binding energies. In the In 3d spectrum . As shown in 2S3 displays clearly two peaks (162.73 and 157.43 eV), which can be attributed to the 4f5/2 and 4f7/2 of Bi3+. Moreover, compared to Bi2S3, the peak positions (163.50 and 158.18 eV) of Bi 4f in 0.05CN/Bi2S3/In2S3 are shifted to higher binding energies. Since the peak of Bi 4f covers the characteristic peak of S 2p, S 2s is added to illustrate the existence of S2−. As shown in 2S3/In2S3 shows three peaks at 221.0, 224.0, and 224.9 eV. Compared with Bi2S3/In2S3, 0.05CN/Bi2S3/In2S3 shows peaks that are slightly shifted to higher binding energies . These results suggest the successful heterogeneous growth of In2S3 and Bi2S3 on the g-C3N4 nanosheets.To study the surface chemical states and chemical compositions of the CN/Bispectrum , the In 3.1.53N4 nanosheets have on the Bi2S3/In2S3 heterostructure, the optical absorption properties of the as-prepared samples were analysed using UV-vis spectroscopy, the results of which are shown in 3N4 shows good light absorption at a wavelength of less than 450 nm. The light absorption of In2S3 and Bi2S3 seem much higher than that of g-C3N4, at a wavelength of 1000 nm. Compared with Bi2S3/In2S3, the absorption edge of the g-C3N4/Bi2S3/In2S3 heterostructure exhibits a distinct red shift, which may originate from the modification effect of Bi2S3/In2S3 on the surface of the g-C3N4 nanosheets. This signifies that a strong interaction is formed between g-C3N4 and Bi2S3/In2S3, which is beneficial to improving the separation efficiency of charge carriers and the stability of the heterostructure. In addition, the band gap energies (Eg) of the samples were calculated using the Tauc equation:α, hν, A and Eg are the absorption coefficient, photoenergy, proportionality constant and band gap, respectively. As shown in 3N4, In2S3 and Bi2S3 are 2.84, 2.2, and 1.30 eV, respectively. In addition, the band gap of Bi2S3/In2S3 is estimated to be 1.26 eV, and the band gaps of 0.01CN/Bi2S3/In2S3 and 0.05CN/Bi2S3/In2S3 are 1.20 and 1.18 eV, respectively. Compared with Bi2S3/In2S3, the band gap of 0.05CN/Bi2S3/In2S3 is narrower, which indicates that the heterostructure of 0.05CN/Bi2S3/In2S3 is more easily excited by visible light and is beneficial for improving photocatalytic performance due to the modification of large holes and defects on the surface of the g-C3N4 nanosheets.To investigate the modification effect that the g-C3.1.655 The PL spectra of g-C3N4, Bi2S3/In2S3 and 0.05 g-C3N4/Bi2S3/In2S3 are shown in − and h+ and the weaker the PL peak intensity is, the slower the recombination rate of the excited e− and h+. Comparing the PL emission spectra of the three materials, the 0.05 g-C3N4/Bi2S3/In2S3 heterostructure shows low fluorescence intensity relative to that shown by g-C3N4 and Bi2S3/In2S3. These results indicate that the efficient interfacial charge transfer between Bi2S3/In2S3 and g-C3N4 hinders the recombination of e− and h+ pairs. In addition, To further understand the reasons for the improvement in the photocatalytic activity of the composite photocatalyst, the PL spectra were measured to investigate the separation efficiency of photo-induced charge carriers.3.23N4 composite catalyst shows the best catalytic activity, which almost completely degrades the dye after 45 min of exposure to light. 3N4/Bi2S3/In2S3 catalyst is 0.02826, which is significantly higher than the values for g-C3N4, In2S3 and Bi2S3. Compared with recently published articles, this study has advantages in degradation efficiency.56–583.33N4, In2S3 and Bi2S3 respectively . From the results obtained and shown in 3N4 (1.95 and −0.89 eV), In2S3 (0.32 and −1.88 eV), and Bi2S3 (−0.35 and −1.65 eV) can be calculated, which facilitate the subsequent analysis of the mechanism of the photocatalyst degradation. 2C2O4 as the reactive species scavengers for ˙OH, ˙O2−, and h+, respectively.59 It can be seen that BQ, IPA and EDTA-2NA all have different degrees of influence on the catalytic performance of the catalyst. Among them, IPA has the greatest degree of influence, with a degradation rate of 28.3%, whereas EDTA-2Na has the lowest degree of influence and a degradation rate of 65.3%. This shows that photogenerated e− have a greater impact on the ternary heterostructured nanocomposite g-C3N4/In2S3/Bi2S3 than h+. 3N4/In2S3/Bi2S3 catalyst. When the catalyst is excited by light, e− transition from the VB to the CB. Due to the difference in electronegativity, the excited e− will be transferred from the CBs of In2S3 and Bi2S3 to the CB of g-C3N4. At the same time, h+ will be transferred from the VB of g-C3N4 to the VBs of In2S3 and Bi2S3, and can also oxidise pollutants. The transfer speed of h+ and e− is improved, and the recombination of photogenerated carriers is suppressed, which improves the photocatalytic performance of the material. It is speculated that the photocatalysis may proceed in the following way:Of these, 3.43N4/Bi2S3/In2S3 catalyst. After repeating the degradation test four times, the degradation performance of the catalyst still reaches 90.9. Therefore, it can be seen that the heterostructure of the composite catalyst not only improves its activity, but also its stability. To further assess whether the structure of the catalyst is damaged after use, PXRD measurements were carried out on the catalyst before and after its use, and the results are shown in 43N4/In2S3/Bi2S3. The g-C3N4/In2S3/Bi2S3 heterostructure catalyst shows significantly improved degradation of RhB compared with the components from which it is made. The reason for the improved photocatalytic performance can be attributed to the increase in the specific surface area of the catalyst, meaning that it has more active sites; the formation of 3D dendritic and porous spherical materials enhances the adsorption performance of the catalyst and the composition of the heterostructure catalyst accelerates the separation of photogenerated carriers, thereby promoting the production of O2−, OH, and h+. The research herein describes the design of a new type of ternary heterostructure catalyst. The disadvantage here is that the decomposition process of the degradants was not able to be analysed in detail, which remains a subject for future work.In this paper, a one-step hydrothermal method was used to synthesise a 3D dendritic and porous spherical ternary heterostructure nanocomposite g-CThe authors declare that they have no competing interests.RA-011-D1RA00729G-s001


With the gradual prolongation of the overall survival of cancer patients, the cardiovascular toxicity associated with oncology drug therapy and radiotherapy has attracted increasing attention. At present, the main methods to identify early cancer treatment-related cardiac dysfunction (CTRCD) include imaging examination and blood biomarkers. In this review, we will summarize the research progress of subclinical CTRCD-related blood biomarkers in detail. At present, common tumor therapies that cause CTRCD include: (1) Chemotherapy—The CTRCD induced by chemotherapy drugs represented by anthracycline showed a dose-dependent characteristic and most of the myocardial damage is irreversible. (2) Targeted therapy—Cardiovascular injury caused by molecular-targeted therapy drugs such as trastuzumab can be partially or completely alleviated via timely intervention. (3) Immunotherapy—Patients developed severe left ventricular dysfunction who received immune checkpoint inhibitors have been reported. (4) Radiotherapy—CTRCD induced by radiotherapy has been shown to be significantly associated with cardiac radiation dose and radiation volume. Numerous reports have shown that elevated troponin and B-type natriuretic peptide after cancer treatment are significantly associated with heart failure and asymptomatic left ventricular dysfunction. In recent years, a few emerging subclinical CTRCD potential biomarkers have attracted attention. C-reactive protein and ST2 have been shown to be associated with CTRCD after chemotherapy and radiation. Galectin-3, myeloperoxidas, placental growth factor, growth differentiation factor 15 and microRNAs have potential value in predicting CTRCD. In this review, we will summarize CTRCD caused by various tumor therapies from the perspective of cardio-oncology, and focus on the latest research progress of subclinical CTRCD biomarkers. Improved early detection methods and the introduction of innovative cancer treatments have allowed a larger number of cancer patients to live longer. There were more than 16.9 million cancer survivors in the United States as of January 1, 2019, a figure that is projected to increase by 30% over the next decade to exceed 22.1 million . RegardlExperts from the American Society of Echocardiography and the European Association of Cardiovascular Imaging define CTRCD as a decrease in left-ventricular ejection fraction (LVEF) of more than 10%, confirmed by repeated cardiac images at 2–3-week intervals, to a value <53% . It shou2, and rises to 48% at 700 mg/m2  is a transmembrane glycoprotein encoded by the proto-oncogene ue cells . Her-2 iue cells . Trastuzue cells . Howeverue cells . Compareue cells . Trastuzue cells . Trastuzue cells .Immune checkpoint inhibitors (ICIs) are a primary focus of research on tumor immunotherapy. A total of seven ICIs have been approved for use by the FDA since 2011, including one cytotoxic T lymphocyte-associated protein 4 inhibitor (ipilimumab), three kinds of programmed cell death protein-1 (PD-1) inhibitors , and three kinds of programmed death ligand-1 (PD-L1) inhibitors  . These dThe mechanism behind CTRCD caused by ICIs is currently unclear. ICIs disrupt tumor immune escape and induce activated T cells to attack tumor cells. The same antigenic epitopes are present on both tumor cells and cardiomyocytes, suggesting that ICI activation of T cells against tumor cells also enhances the cross-reaction with cardiac antigens .Radiation-induced heart disease (RIHD) is one of the most serious long-term complications of radiotherapy for thoracic tumors. The emergence of RIHD has led to a reexamination of the benefits and potential risks of radiation therapy. The incidence of HF after contemporary conformal radiotherapy is positively correlated with the mean radiation dose to the heart . The likThe troponin complex is key to the regulation of skeletal muscle and cardiac muscle thin filament contraction. Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are expressed exclusively in the myocardium. cTn is released after cardiomyocyte necrosis, and is highly sensitive and specific for diagnosing a myocardial infarction. Increased circulating cTn can precede changes in echocardiographic indicators, and can therefore help in the early diagnosis of subclinical CTRCD . High-seTn is one of the most popular biomarkers for the prediction of CTRCD. The elevation of Tn before the onset of cardiac symptoms in cancer patients is indicative subclinical functional and myocardial damage, and is closely related to all-cause mortality in cancer patients . cTn is Multiple studies have shown that Tn levels do not significantly change during trastuzumab monotherapy –38. Of 5Tn is the cornerstone of cardiotoxicity screening during ICI therapy. Patients with acute HF during ICI treatment had increased hs-TnT levels and a severely reduced LVEF . HoweverChanges in Tn in patients receiving thoracic radiotherapy has been of recent interest. In a cohort study of 87 patients treated with radiotherapy for breast cancer, lung cancer or mediastinal lymphoma, there was a downward trend in hs-cTnT from pre-radiotherapy to the completion of radiotherapy, especially in the subgroup that received an anthracycline and trastuzumab. This trend was thought to be related to cardiotoxicity caused by the previous treatment . HoweverBased on existing studies, cTn can identify early myocardial damage caused by chemotherapy or ICIs and predict CTRCD. However, Tn is inconsistently predictive of radiation-induced cardiotoxicity.in vivo and in vitro and is more popular in clinical practice. Negative BNP and NT-proBNP are used as exclusion criteria for acute and chronic HF, and both are widely used in the diagnosis and prognostic assessment of HF.BNP, a neuroendocrine hormone secreted by ventricular myocytes, responsively increases when the ventricular wall stretches due to the increased volume or load stress caused by HF, resulting in beneficial effects such as sodium regulation, diuresis and vasodilation . N-termiThere have been numerous reports on the detection of subclinical CTRCD by BNP and NT-proBNP. NT-proBNP is closely related to long-term mortality in select cancer populations, and its serum level gradually increases with tumor progression . In a stNT-proBNP successfully predicted the risk of CTRCD in a prospective cohort study that included 323 breast cancer patients who received anthracycline or trastuzumab, with a maximum 3.7-year follow-up . BaselinThere are few studies that study the use of BNP or NT-proBNP in the prediction of ICI-related cardiac dysfunction. In a study of 30 patients with ICI-related cardiotoxicity, serum BNP levels were elevated in all 14 patients they were measured in . In anotElevated BNP levels after radiotherapy have been reported in multiple works, suggesting that it may be a potential biomarker for predicting RIHD. In one study, 25 patients with thoracic cancer received a mean cardiac radiation dose of ≥20 Gy, and elevated BNP levels were detected at the end of radiation therapy and at their first follow-up (1 to 2 months post-radiation) . Due to Based on existing studies, BNP/NT-proBNP can effectively predict chemotherapy-induced cardiac dysfunction, especially delayed HF. BNP/NT-proBNP also has potential in the prediction of targeted therapy or radiation-related cardiac dysfunction.Myeloperoxidase (MPO), an enzyme primarily secreted by neutrophils, plays a vital role in the pathogenesis of atherosclerosis, congestive HF, hypertension and other cardiovascular diseases . ElevateKy et al. first described the utility of MPO in predicting early CTRCD . The serC-reactive protein (CRP) is an acute-phase protein that is secreted by the liver during inflammation, and whose expression is regulated by interleukin-6 and tumor necrosis factor-α. A high serum level of CRP (>10 mg/L) can predict the mortality of patients with acute decompensated HF one year after discharge . High-seCRP/hs-CRP has recently emerged as an inexpensive, readily available and easily repeatable potential biomarker for the identification of early CTRCD. Onitilo et al. monitored cardiotoxicity during trastuzumab treatment in 54 patients with positive Her-2 breast cancer who had received standard chemotherapy . When thCRP has recently been shown to have important predictive value in tumor immunotherapy. CRP is a prognostic biomarker for ICI treatment , 64. Meths-CRP may also be a biomarker for radiation-induced cardiac dysfunction. Canada et al. found reported increased hs-CRP in 64% of 25 patients 1.8 years after the completion of thoracic radiotherapy . AbnormaCRP/hs-CRP demonstrated good CTRCD screening ability in the setting of chemotherapy, targeted therapy and immunotherapy. Of the emerging CTRCD biomarkers, CRP/hs-CRP has a relatively high predictive value and is expected to be widely used in clinical practice in the future.ST2, a member of the interleukin 1 receptor family, is highly expressed when cardiac muscle cells are subjected to mechanical stress. The soluble receptor form of ST2 (sST2) is present in human circulation, and is an effective indicator of myocardial cell extension and fibrosis. sST2 levels are closely associated with sudden cardiac death and long-term mortality in HF patients , 71.Few studies have addressed the predictive value of ST2 for CTRCD. Sawaya et al. followed 81 Her-2-positive breast cancer patients treated with anthracyclines followed by taxanes and trastuzumab or radiation for 15 months . ST2 levGrowth differential factor 15 (GDF-15) is a member of the transforming growth factor beta superfamily that has cell protection, anti-apoptosis and anti-hypertensive properties. GDF-15 is upregulated in the setting of inflammation, oxidative stress, tissue hypoxia and cell injury . High sePlacental growth factor (PlGF) is a member of the vascular endothelial growth factor family. PlGF promotes the angiogenesis of ischemic heart and limb tissue by specifically binding with the Flt-1 receptor, and also participates in the pathologic processes of atherosclerosis and arthroinflammation , 79. It in vitro 24 h after radiation exposure  are highly conserved, single-stranded non-coding RNAs approximately 22 nucleotides in length that bind to messenger RNAs to silence gene expression. miRNAs participate in the regulation of approximately 30% of essential human gene expression, meaning that miRNAs regulate a large number of cell metabolic processes such as proliferation, apoptosis and metastasis . The commiRNAs have recently been used to detect subclinical chemotherapy-related cardiotoxicity. Leger et al. observed a sharp increase in plasma miR-29b and miR-499 levels within 6 to 24 h of chemotherapy in children with an anthracycline chemotherapy-associated acute myocardial injury, and a significant correlation between elevated miRNAs and anthracycline dose . LakhaniRecent studies suggest that increased levels of miR-130a during anthracycline plus trastuzumab treatment are an independent predictor of cancer treatment-related cardiotoxicity . NotablymiRNAs have been found to be upregulated in animal models of autoimmune myocarditis, and correlated with the development of autoimmune myocarditis . miRNAs Numerous studies have noted a close relation between miRNAs and RIHD. Hawkins et al. measured the circulating miRNA levels of 63 patients with NSCLC before radiotherapy and found that elevated miRNAs, such as miR-574, were correlated with a greater risk of radiation-related cardiotoxicity . In addiIn sum, miRNAs are a new tool for detecting early CTRCD. miRNAs profiles can provide a great deal of information about CTRCD, especially in those who have received chemotherapy and radiotherapy.There are many other clinical biomarkers that may be useful in the prediction of CTRCD. Glycogen phosphorylase BB (GPBB), one of the subtypes of glycogen phosphorylase, is mainly distributed in the heart and brain. GPBB is the key enzyme in glycogenolysis, supplying energy to cardiomyocytes during myocardial ischemia . GPBB isAnthracycline-induced CTRCD is closely associated with oxidative stress and endothelial dysfunction. The arginine–nitric oxide metabolic pathway plays an important role in these two pathophysiological processes. Arginine–nitric oxide metabolites such as asymmetric dimethylarginine and N-monomethylarginine can inhibit the activity of endothelial nitric oxide synthase and cause DNA damage, myocardial cell apoptosis and endothelial cell dysfunction . In a foPrevention strategies for CTRCD currently include: (1) Correction of pre-existing cardiovascular risk factors; (2) Direct reduction of cardiotoxicity: through a reduced cumulative dose of chemotherapy drugs, use of anthracycline liposomes and altered administration regimens; (3) Cardioprotectants such as dexrazoxane, which has been approved by the FDA for the cardiac protection of metastatic breast cancer patients receiving high doses of doxorubicin. (4) Cardiovascular support drugs such as angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, selected beta blockers and statins have been shown to prevent CTRCD . Tn provIn this review, we emphasize the vital role of serum biomarkers in the detection of subclinical CTRCD. We summarized the progress of research on two classical biomarkers (Tn and BNP) and several emerging biomarkers  in the prediction of early CTRCD. Classical biomarkers have good sensitivity and specificity, low cost, and provide quantifiable and reproducible data. A large number of studies have confirmed that classical markers can predict the risk of CTRCD and guide further treatment. Emerging biomarkers are involved in many biological processes, and their addition may further enhance the utility of biomarkers in the management of CTRCD. For example, CRP and ST2 are associated with inflammation, galectin-3 is associated with cell proliferation, MPO and GDF-15 are associated with oxidative stress, PlGF is associated with angiogenesis and miRNAs are associated with apoptosis. However, disadvantages of emerging biomarkers are their high cost and low popularity .In addition to blood biomarkers, cardiac imaging has been widely used in the detection of subclinical CTRCD. Echocardiography, currently the most commonly used imaging tool for detecting CTRCD in clinical practice, is non-invasive, highly repeatable, simple and safe. LVEF is the most widely used cardiac function indicator in echocardiography, and can independently predict the short-term and long-term mortality of CTRCD. However, due to the early compensatory response of LVEF after heart injury, subclinical CTRCD cannot be accurately detected by LVEF. Strain-echocardiography is a new tool for evaluating myocardial deformation. GLS, as assessed by speckle-tracking echocardiography, can accurately measure early myocardial changes caused by cancer treatment. A 10–15% reduction in GLS is the most effective predictor of early CTRCD . A largeMost clinical studies on the prediction of early CTRCD focused on the traditional biomarkers Tn and BNP, with few studies on emerging markers. Future studies can be improved in the following ways: (1) a longer follow-up time will provide valuable data for improve the predictive power of biomarkers for late cardiotoxicity; (2) increasing the sample size will improve study accuracy; (3) the direction of cardiotoxicity caused by targeted therapy or ICIs should be further explored. Genetic testing, human stem cell-derived cardiomyocytes and artificial intelligence have all been used to predict subclinical CTRCD .In conclusion, the early diagnosis, treatment and prognostic assessment of CTRCD in the era of precision medicine all require close cooperation between oncologists and cardiologists. Emerging biomarkers have strong potential to predict subclinical CTRCD and provide direction for future cardio-oncology.All authors contributed to the conception, development, and critical appraisal of this manuscript. All authors contributed to the article and approved the submitted version.This study was funded by Natural Science Foundation of Liaoning Province (No. 2012049) and Youth Foundation of Dalian (Nos. 2017QN006 and 2019QN028).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


ADHD is a highly consequential disorder that is estimated to affect 2.5% of the adult population. Emerging models of psychopathology posit that disorders like ADHD can be usefully situated within general models of individual differences in personality, such as those recently implemented in the DSM and ICD for the diagnosis of personality disorder. Previous research and systematic reviews have linked adult ADHD to the personality traits Conscientious Inhibition and Negative Emotionality. However, there have been some inconsistencies in the literature and research embedding ADHD-personality connections in the DSM-5 and ICD-11 personality disorder models has been limited. The goal of this paper was to systematically review associations between adult ADHD and personality traits, organized within a maladaptive five factor framework.A comprehensive literature search yielded 13 papers whose effects were meta-analyzed.Results supported associations between ADHD and low Conscientious Inhibition and high Negative Emotionality. However, interesting patterns of variability were observed, potentially related to issues such as instrumentation and facet variation.Results support the clinical application of personality assessment for suggesting risk for ADHD symptoms, and point to important directions for further research. Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric disorder –3. AlthoMost research on personality and psychopathology organizes individual differences in the form of the Five Factor Model , which iSeveral previous reviews have documented associations between FFM personality traits and ADHD –19. ThesNeuroticism which refers to the extent of negative emotions, i.e., sadness, fear, hostility, and emotional lability that the individual experiences [Extraversion concerns how outgoing or talkative the individual is in most situations. Core traits are sociability, assertiveness, positive affect, and activity level [Openness to experience describes the depth and breadth of an individual’s intellectual, artistic, and experiential life, with key facets such as aesthetic sensitivity, intellectual interests, and imagination [Agreeableness concerns the extent of the individual’s motivation for prosocial behavior and pleasant interpersonal relationships. Important traits are compassion, trust, and politeness [Conscientiousness refers to the individual’s level of organization, ability to complete tasks, and persistence in achieving long-term goals. Key concepts are orderliness, self-discipline, and reliability [The FFM consists of the following five factors: eriences . Individeriences . Extravety level . Low Extty level –26 and ety level . Opennesgination . Althouggination . Agreeabliteness . Individliteness  . Agreealiteness , 30. Malliteness . Conscieiability . Howeveriability , 32; andiability –35.Research has shown that multiple models of both normal-range and maladaptive personality traits can be integrated into the structure of the FFM –38. For Conceptualizing ADHD as a dimension or set of dimensions that can be placed within a general, evidence-based model of maladaptive personality traits has a number of potential clinical advantages –44. For Four previous studies summarize associations between personality traits and adult ADHD –19, 47. In summary, the aim of this study was to quantify associations between ADHD and the traits of an Integrated FFM to better understand how ADHD fits into evidence-based models of personality and psychopathology, and ultimately enable improved clinical practice and research. Given the existing body of research in adult populations, we focused on traits from the FFM, DAPP, HEXACO , and TCILiterature searches were conducted in November 2019 via Cochrane, PubMed, PsychInfo and SCOPUS using the following keywords: (ADHD OR ADD OR ADDH OR Attention Deficit Disorder with Hyperactivity) AND . The reference sections of each article retrieved was searched manually for any potentially relevant studies. Included studies were a) written in English; b) published after January 1, 2000; c) contained adult cases with a diagnosis of ADHD according to DSM-IV or DSM-5; d) used validated measures to assess adult ADHD; e) used established dimensional personality measures ; and f) presented results in a format that allowed for straightforward conversion to the FFM i.e. into the Integrated Five-Factor Model . This process resulted in 14 papers that sampled adult patients with ADHD , 55–61. All formal ADHD diagnoses were based on the DSM criteria, although different instruments were used to assess current and historical symptoms and impairments. All data included in this analysis examined group differences as they relate to personality traits. Control groups included community samples, non-clinical parents of children with ADHD, blood donors, clinical groups without ADHD, and population norms extracted from manuals Table . In five2 was used to evaluate the heterogeneity of mean effect sizes. An I2 value above 50% can be interpreted as meaningful heterogeneity around the mean effect size [Meta-analysis was used to aggregate associations of personality traits and ADHD in Meta-Essentials , 64. Groect size .The 14 papers were ranked for scientific quality according to an adaptation of QUADAS . QUADAS Thirteen original articles consisting of 2023 unique adult subjects diagnosed with ADHD and 16,835 control participants, were included in this meta-analysis. Mean age ranged from 21.6 to 42.8 years; 54% of the included population identified as male. Most of the clinical cases of ADHD were recruited through psychiatric clinics, either general or specialized centers  for Openness to d = 1.11 (large) for Negative Emotionality , 69 Fig. The effEven though the combined effect sizes for Negative Emotionality and Conscientious Inhibition were large, there was significant variability in the ADHD populations within these personality domains. Effect sizes for Negative Emotionality ranged from d = 0.50 (medium to large) to d = 2.06 (very large) Fig. . An even2 is a measure for the proportion of observed variance that reflects real differences in effect size. It is expressed as a percentage with a range from 0 to 100% [2 for FFM Negative Emotionality was 47% and I2 for FFM Agreeable Inhibition was 64%.The I to 100% . All effNegative Emotionality and low Conscientious Inhibition. Positive Emotionality and Agreeable Inhibition have somewhat smaller, although significant, associations with adult ADHD. These results are consistent with the review from Gomez et al. [The results of this systematic, quantitative review suggest a robust connection between adult ADHD and the IFFM personality domains z et al. , with thConscientious Inhibition consists of features that are also implicated in the core symptoms of ADHD. These features are conceptualized in ADHD as difficulties in executive functions or self-regulatory processes [behavioral inhibition, consisting of: a) inhibition of pre-potent responses, b) stopping ongoing responses, and c) interference control, can be seen as a superordinate factor that affects several cognitive and behavioral modalities, eventually manifesting themselves in specific symptoms commonly found in ADHD. This construct is largely commensurate with Conscientious Inhibition as conceptualized in trait measures, thus providing a bridge between neuropsychiatric and quantitative trait approaches to conceptualizing underlying deficits in ADHD [Low rocesses , 72. Barrocesses  proposed in ADHD , 48, 74.Negative Emotionality is elevated across many psychiatric disorders and is highly predictive of psychological and physical comorbidity as well as general quality of life [ of life , 48. Alt of life . There i of life –78.2 measure, described above, indicates that there is a high degree of heterogeneity between studied populations within the different personality domains in the meta-analysis. Ideally, subgroup or moderator analyses would be performed to explain this variation. However, the number of studies available for this meta-analysis was too small to test moderation. Nevertheless, some potentially reliable patterns were observed.Significant variability was observed in effect sizes between and within samples in the current review, as well as between instruments. For example, the high percentage in the IFirst, when specific measures of FFM were extracted for separate analysis, heterogeneity decreased. This suggests more consistency when personality traits were measured with FFM instruments. One particularly important source of variability may have to do with differing facet models across those instruments. Facet variability is complicated by the interstitial nature of some traits, which leads different models to place similar facets on different domains. For instance, we conceptualized TCI Self-transcendence as an aspect of Negative Emotionality, although it also shares some features with Conscientious Inhibition. Future work exploring a broader range of traits, and conceptualizing personality at the level of facets, would shed significant light on this issue.Second, stronger effects with psychopathology can generally be expected with maladaptive as opposed to normal range personality measures . As malaA third source of variability involves ADHD presentation, given that traits may differentially relate to inattentive, impulsive and hyperactive features , 51, 58.Overall, these findings support the emerging view that personality, personality disorders, and neurodevelopmental disorders can be conceptualized within an integrated and evidence-based dimensional trait system. This supports the clinical application of personality trait assessment models according to the DSM and ICD diagnostic systems to broaden the clinical description of adult ADHD, as well as research on the shared etiological factors between personality variables and ADHD.Categorical psychiatric diagnoses are fraught with high comorbidity, complicating the clinical picture and reducing treatment specificity. Dimensional models provide an opportunity to integrate comorbidity into a more comprehensive and individualized clinical description, which makes treatment planning more in line with current clinical praxis. The current review suggests that the features of ADHD can be economically situated within evidence-based models of personality and psychopathology. As such, the clinical use of personality trait measures and the emerging dimensional personality models included in the AMPD and the ICD-11 proposal provide opportunities to implement a more individualized approach for patients with problems related to hyperactivity, impulsivity, and inattention. Specifically, multidimensional trait profiles may help clinicians estimate long-term risk for psychosocial consequences of ADHD, as well as the likelihood of other comorbid conditions. They also help provide explanations for heterogeneous clinical presentations and point to appropriate pathways for intervention –43, 79.In clinical practice it is useful to rely on heuristics to make efficient clinical decisions . For exaWhite Educated Industrialized Rich and Democratic). Greater diversity in samples is needed to add confidence to these findings and enhance generalizability.The literature on associations between adult ADHD and personality traits is scarce, thus limiting the degree to which the current results can provide robust information about these links. The existing literature, while sufficient to quantitatively summarize connections between adult ADHD and IFFM trait domains, limited our ability to test moderators such as ADHD subtype, personality measure, or various sample features, and it necessitated inclusion of measures with varying connection to the FFM or DSM/ICD personality disorder proposals. Some of our conclusions were based on assumptions about how to organize facets into maladaptive five factor domain , 47 thatPsychiatric nosology is in a transition from legacy diagnostic categories to evidence-based models of individual differences that closely resemble personality traits , 81. Res


There is a debate about the measure of IQ in children with ADHD. Some studies report that, compared to static assessment procedures, dynamic assessment of intelligence can better measure cognitive modifiability and plasticity. The present study was designed to examine children belonging to different ADHD subtypes  in terms of both static (WISC scores) and dynamic measures (Modifiability index). Thirty-four children  were compared to a sample of 27 typically developing children. Results indicate that only the inattentive and the combined subtypes, compared with the normative sample, show lower IQ scores. The ADHD-I group presents generally low WISC scores and ADHD-H presents generally high WISC scores. Moreover, the ADHD-C group shows a low static score and a high dynamic score, indicating a wide breadth of Vygotskian children’s zone of proximal development. Static and dynamic measurements together can indeed be considered a comprehensive examination of intelligence levels in ADHD children and may be essential in predicting learning capacities. Traditionally, the measures of intelligence are obtained by testing either a ratio of mental age to chronological age or a score of deviation from an expected test performance by age. Such measures are referred to as “static assessment procedures,” and one of the major characteristics is that they emphasize previously acquired knowledge in terms of intelligence or achievement scores; they do not incorporate modifications aimed at increasing levels of performance into their procedure .Dynamic measures of intelligence are generally obtained by administrating novel problem-solving tasks to the subjects, supplying them with gradual and balanced assistance that progressively discloses the solution of the problem, and determines the amount of aid the learner needs to be able to solve the problem. This aid is inversely proportional to the modifiability index. The modifiability index, that is the general propensity to change, can be considered a more appropriate measure of intelligence .Evidence on the effectiveness of dynamic testing confirms that it has considerable value for predicting children’s learning potential. Both, age and static measures of intelligence are positively related to the breadth of Vygotskian children’s zone of proximal development as determined by dynamic testing . The perIt is likely that ADHD has a uni-directional effect on intelligence in a number of ways . The impDue to the controversy about the measure of IQ in children with ADHD, the present study was designed to examine children belonging in each of ADHD subtypes and typically developing students in terms of both static and dynamic measures. More specifically, the first question addressed in the study was whether a precise identification of ADHD subtypes could help us to better understand the role of each of these on static measures of intelligence, with reference to both quality and quantity of performance. The second question was to analyze if each subtype of ADHD shows different levels of dynamic measures, thus giving the possibility to predict children’s learning potential. Moreover, the answers to these questions should allow us to understand which subtype performs poorly when left alone (static measures) and better when given appropriate instructional intervention (dynamic measures), in other words, which ADHD subtype presents a wider breadth of Vygotskian children’s zone of proximal development as determined by dynamic testing.The participants in this study were selected from a sample of 987 students attending public schools in Lombardy, a region of Northern Italy, and Sicily, a region of Southern Italy. Students ranged in age from 8 to 10 years and were attending either the 4th or 5th grade of primary school. A wide sample of schools had been involved in previous on-the-job training courses addressed to teachers, who were contacted and asked to collaborate in the investigation. The procedure described below was followed in all schools that decided to participate. Inclusion criteria for the ADHD group were: (1) a positive screening for ADHD based on the Deficit Attention Teacher Scale DATS; ; (2) a nEighteen items compose DATS, corresponding to the symptom domain of ADHD as described in the Diagnostic and Statistical manual of Mental Disorders DSM-5; . Two scoThe sample of the initial 987 students who obtained DATS and DBDRS scores in the normal range, who were not included in any clinical group, and of children not diagnosed by the school psychologists with behavioral, emotional, and/or relational problems constituted the basis to form the TD group. Twenty-seven students were randomly extracted from such a sample. Their gender and age were considered in order to choose students who could constitute a group whose boy/girl ratio and whose mean age matched the clinical groups. Among TD children who were selected based on gender and age criteria, only children who also have DATS and DBDRS scores as 0 and had no clinical disorders, were included in the final TD group. The characteristics of ADHD and control children are summarized in F = 21.60, p < 0.001] and on items of hyperactivity subscales . The gender effect within the ADHD groups was not statistically significant.As expected, the TD group differed significantly on the items of distractibility . Follow-up t-tests revealed that children with ADHD-H presented higher IQ scores than children with ADHD-I , children with ADHD-C  and normally developing children . Children with ADHD-I showed lower IQ scores than children with ADHD-H  and TD children .With reference to the full scale WISC IQ, the one-way ANOVA indicated that there is a main effect of Group . Follow-up t-tests revealed that children with ADHD-I presented lower information scores than children with ADHD-H , children with ADHD-C  and normally developing children .With reference to information, the one-way ANOVA indicated that Group show significant statistical effect [F = 3.32, p < 0.02, η2 = 0.09. Follow-up t-tests revealed that children with ADHD-I presented lower vocabulary scores than children with ADHD-H , children with ADHD-C  and TD children . In this case ADHD-C, ADHD-H, and TD children did not differ.With reference to vocabulary, the one-way ANOVA indicated that Group show significant statistical effect, F = 7.81, p < 0.01, η2 = 0.23. Follow-up t-tests revealed that children with ADHD-I presented lower similarities scores than children with ADHD-H , children with ADHD-C  and TD children . Children with ADHD-H presented higher similarities scores than children with ADHD-I , children with ADHD-C  and TD children . In this case ADHD-C and TD children did not differ.With reference to similarities, the one-way ANOVA indicated that Group show significant statistical effect, F = 3.53, p < 0.02, η2 = 0.09. Follow-up t-tests revealed that children with ADHD-I presented lower symbol search scores than TD children . Furthermore children with ADHD-C presented lower symbol search scores than TD children . In this case ADHD-H and TD children did not differ.With reference to symbol search, the one-way ANOVA indicated that Group show significant statistical effect, F = 3.62, p < 0.01, η2 = 0.12) and with reference to the test of the transfer phase, F = 5.0, p < 0.01; with reference to transfer phase, follow-up t-tests revealed that children with ADHD-I presented lower dynamic testing scores than children with ADHD-H , and TD children . Children with ADHD-C showed lower IQ scores than children with ADHD-H .With reference to the full scale of dynamic testing, the one-way ANOVA indicated that Group show significant statistical effect both with reference to the full scale , and children with ADHD-C .With reference to the full scale of dynamic testing, children with ADHD-H showed higher dynamic testing scores than children with ADHD-I  and better when given appropriate instructional intervention (dynamic measures), in other words, which ADHD subtype present a wider breadth of Vygotskian children’s zone of proximal development as determined by dynamic testing. In the present study, the classification of participants was based on standardization measures of previous works  in whichThe present study indicated that only the ADHD-I and ADHD-C groups, when compared with the TD group, show lower scores in comprehension, picture completion, picture arrangement, block design, and object assembly. By considering separately ADHD subtypes, more information emerged clarifying some discrepancies between the different authors in the field of static measures. Some studies that adopted mixed groups, generally show that students with ADHD have slightly lower IQs than control samples. The distinction into different subtypes helps us to illustrate that this can be applied only to ADHD-I which presents general low WISC scores as opposed to ADHD-H which presents general high WISC scores. Other studies indicated that the distribution of estimated Full Scale IQs (FSIQ) for each of the three groups of children did not differ significantly from a normal distribution, with most children (more than 50%) in each group scoring in the average range . These rHowever, the results of the present study should be evaluated with caution, because the sample size is small. Thus, future research should examine dynamic and static tests using a larger sample size to ensure adequate power. Despite this limitation, this study is an indication of the importance of a wider evaluation of cognitive performance in predicting learning capacities in ADHD children.Moreover, static and dynamic test assessment of cognitive ability has been also investigated in other domains, such as autism spectrum disorder (ASD). As regards to this, some studies have examined different methods of modeling or investigating cognitive ability among individuals with ASD, providing insights into the cognition-based neural dynamics of subjects with ASD. For example, a recent study has indicated that coupling strength can be a potential biomarker to identify cognitive status at a higher discrimination rate in ASD . AnotherTwo main conclusions emerge from the present study, the first is that static and dynamic measures together can give us more information about the intelligence of children with ADHD. The second is that although the ADHD occurs in three different clinical features (the three ADHD subtypes), it is necessary to reconsider the inclusion of ADHD-H subtype in a different framework in which behavioral but not cognitive problems are considered, given that only the ADHD-I and ADHD-C groups have shown a poor performance in comprehension, picture completion, picture arrangement, block design, and object assembly.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Messina. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.RF conceived and designed the analysis and performed the analysis. TC and GT collected the data and contributed data and analysis tools. GT wrote the paper. All authors approved the manuscript.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder in children. Several scales are available to evaluate ADHD therapeutic effects, including the Swanson, Nolan, and Pelham (SNAP) questionnaire, the Vanderbilt ADHD Diagnostic Rating Scale, and the visual analog scale. However, these scales are subjective. In the present study, we proposed an objective and automatic approach for evaluating the therapeutic effects of medication in patients with (ADHD). The approach involved using movement quantification of patients’ skeletons detected automatically with OpenPose in outpatient videos. Eleven skeleton parameter series were calculated from the detected skeleton sequence, and the corresponding 33 features were extracted using autocorrelation and variance analysis. This study enrolled 25 patients with ADHD. The outpatient videos were recorded before and after medication treatment. Statistical analysis indicated that four features corresponding to the first autocorrelation coefficients of the original series of four skeleton parameters and 11 features each corresponding to the first autocorrelation coefficients of the differenced series and the averaged variances of the original series of 11 skeleton parameters significantly decreased after the use of methylphenidate, an ADHD medication. The results revealed that the proposed approach can support physicians as an objective and automatic tool for evaluating the therapeutic effects of medication on patients with ADHD. Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder; it affects 3–5% of children worldwide . The lonIn recent years, technology of motion detection has advanced to an extent that the device can precisely record data for long periods. For more detailed and objective motion analysis in clinical settings, marker-based systems such as a three-directional motion analysis system and accelerometer are employed. Studies have used many three-dimensional motion analysis devices, such as the VICON motion system in patients with hip osteoarthritis and in those with iliotibial band syndrome or Optotrak to detect the range of motion in healthy participants ,16,17. Hnot at all) to 3 (very much). ADHD has three subtypes, which are diagnosed depending on the symptoms at presentation: inattentive (ADHD-I: inattentive symptoms and few or no hyperactive symptoms), hyperactive/impulsive (ADHD-H: hyperactive or impulsive symptoms and few or no inattentive symptoms), or combined (ADHD-C: both inattentive and hyperactive symptoms). Written informed consent was obtained from a family member or legal guardian of each participant. This study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUIRB-SV(I)-20190060).We included 25 children with ADHD. They were examined by a pediatric neurologist or psychiatrist and were asked to sit on a medical chair for video recording. Children with a history of epilepsy, intellectual disability, drug abuse, head injury, or psychotic disorders were excluded. ADHD diagnosis was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria, and the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV) was used to evaluate ADHD severity. The 26 items of SNAP-IV include the 18 ADHD symptoms (nine for inattentiveness and nine for hyperactivity/impulsiveness) and 8 oppositional defiant disorder symptoms specified in the DSM-IV. Items were rated on a 4-point scale, ranging from 0  defines how data points in a time series are related, on average, to the preceding data points . The ACFt test. p < 0.05 was considered as statistically significant.All statistical analyses were conducted using SAS . Data are presented as means ± standard deviation. The values of SNAP scales and each feature before and after treatment were compared using a two-tailed paired p = 0.2783) and 37.71 ± 12.00 vs. 31.64 ± 14.75 (p = 0.0868), respectively. The mean durations of analyses before and after treatment were 294.19 ± 122.84 and 264.77 ± 72.39 s, respectively. The SNAP scales from the parents and teachers before and after 1 month of medication use did not differ significantly. However, hyperactivity subscales from parents and teachers and the oppositional subscale from teachers were significantly lower after 1 month (The mean age of the 25 enrolled patients (21 boys and 4 girls) was 8 years 4 months ± 2 years 6 months. All boys had ADHD-C; two girls had ADHD-C, and two girls had ADHD-I. The SNAP scores obtained from the parents and teachers before and after 1 month of methylphenidate use were 42.21 ± 12.41 vs. 37.07 ± 13.77 ( 1 month .In this study, through the analysis of ADHD patients’ skeletons, we found four features corresponding to the first autocorrelation coefficients of the original series of four skeleton parameters; moreover, 11 features each corresponding to the first autocorrelation coefficients of the differenced series and the averaged variances of the original series of 11 skeleton parameters demonstrated a significant decrease after 1 month of methylphenidate use. Note that for each of four features corresponding to the first autocorrelation coefficients of the original series, the decrease in mean value means a decrease in the positive first-order autocorrelation of corresponding skeleton parameter’s original series . For eacThe SNAP questionnaire was originally developed to assess ADHD symptoms according to the DSM-III ,32. AlthOpenPose is a method of localizing anatomical key points or “parts,” and it has largely been employed for identifying an individual’s body parts. This method has been used in the diagnosis and monitoring of Parkinson’s disease , epilepsThere is debate on the effects of methylphenidate for children with ADHD. Storebø and colleagues investigated the beneficial and harmful effects of methylphenidate as treatment for children and adolescents with ADHD ,45. OnlyThis study has some limitations. First, although the autocorrelation and variances of our measurements by OpenPose before and after 1 month of methylphenidate use in patients with ADHD differed significantly, the sample size was relatively small. Second, most of our cohort had ADHD-C; thus, our results may not be generalizable to all ADHD subtypes. Future studies should include a higher number of patients with different subtypes to more accurately characterize the medication effects on the three subtypes. In addition, a more accurate characterization of the different drugs in the three subtypes is also necessary. Third, children’s movements in the consulting room may be affected by uncontrollable factors, such as food intake on the day of assessment, sleep quality before the assessment, and emotion. Future studies should include a questionnaire to investigate the relationship between these confounding factors and children’s movements. Fourth, there was no placebo drug given to the patients in our study. We are not sure whether the causes of change of movement in patients are from methylphenidate or a placebo effect. In the future, an unbiased assessment of methylphenidate effect with a placebo design should be performed.Most patients with ADHD have ADHD-H or ADHD-C subtype and hyperactive behaviors. In the present study, autocorrelation coefficients of the original and differenced series and averaged variances of the original series of each skeleton parameter after 1 month of methylphenidate use were used for objective evaluation of the treatment effects. OpenPose was found to be an objective and potential method for evaluating the therapeutic effects of ADHD medication, particularly in patients with ADHD-H and ADHD-C. Our proposed method appears to outperform SNAP scales in monitoring ADHD symptoms after medication use.


Bartonella spp. dynamics, we sampled bats and bat flies across 15 roosts in Costa Rica. PCR indicated prevalence of 10.7% in bats and 29.0% in ectoparasite pools. Phylogenetic analysis of 8 sequences from bats and 5 from bat fly pools revealed 11 distinct genetic variants, including 2 potentially new genotypes.To determine  Bartonella, the causative agent of bartonellosis, is a genus of gram-negative bacteria. Bartonellosis causes a range of symptoms from severe to life-threatening . Clinical syndromes from Bartonella infections include trench fever (B. quintana), cat scratch disease (B. henselae), and Carrion’s disease (B. bacilliformis)  . Samples positive by PCR were sequenced for confirmation.In 2018, we nonlethally sampled 321 bats (18 species) by using hand nets, mist nets, and harp traps across 15 roosts throughout Costa Rica  Figure. Bartonella species, 12 Bartonella sequences from bats and bat flies in Costa Rica , manually checked in MEGA X (https://www.megasoftware.net), and further refined with alignment refinement tool Gblocks version 0.91b (http://molevol.cmima.csic.es/castresana/Gblocks/Gblocks_documentation.html). We constructed the global phylogenetic tree by using Bayesian Markov chain Monte Carlo analyses  with 1 million generations and a burn-in fraction of 25% and determined the parameters for the nucleotide changes (MEGA X).To create global phylogenies, we trimmed obtained consensus sequences to 768 bp and aligned them to 45 genetic sequences: 28 from known Bartonella prevalence from all samples, determined by PCR, was 14.3% (45/314), 10.7% (27/252) for bats and 29.0% (18/62) for ectoparasite pools  and Túnel Arenal (GenBank accession no. MW115628) at opposite ends of the country  in Emus Cave clustered in 4 distinct clades. In addition, Carollia perspicillata bats, the most sampled species in our study, carried Bartonella with sequences from 6 distinct clades. This finding suggests that >1 Bartonella strain is circulating within bat species, even within the same cave.We also found a high level of diversity of  species . For exaBartonella sequences we detected did not cluster with Bartonella species known to cause infection in humans and other animals and did not significantly overlap with sequences from any globally identified species (Bartonella spillover from bat and bat fly species to other animals and humans, further analyses should be conducted.When assessing spillover risk to humans and domestic animals, we found that the  species . To fullBartonella species to be diverse, prevalent, and potentially widely shared among species of bats and bat flies in Costa Rica and Mesoamerica. We expanded existing scientific knowledge on the prevalence and diversity of Bartonella in bats and bat flies in Costa Rica by including species that were not previously tested and described as positive by PCR for these bacteria. We also described 2 new Bartonella genotypes through phylogenetic analysis. Information about the dynamics of Bartonella in its natural hosts can be used to predict and avert further Bartonella emergence.In conclusion, we found Bartonella spp. and GenBank accession numbers and distribution of 11 genetic variants of Bartonella spp. in Costa Rica, 2018.Roost sites and number of bats sampled per roost for


Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels.Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study.Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10–15-point change on the ADHD-RS-5, and a 0.2–0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease  of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful.Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context.Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556. Clinical trials of psychotherapeutic drugs typically use detailed psychometric instruments to assess patients with respect to symptom severity and functional impairment. However, many treating physicians are relatively unfamiliar with these detailed, comprehensive item-by-item assessments, and routinely use instead the brief, holistic Clinical Global Impressions (CGI) scales when conducting patient evaluations (Busner and Targum Although no attention-deficit/hyperactivity disorder (ADHD)-specific CGI subscale currently exists, as a holistic clinical assessment, the CGI generalizes well to a variety of psychiatric conditions, has been demonstrably reliable, and is suitable for routine clinical use . While there is no universally agreed upon or standardized definition of what constitutes clinically meaningful change, it encompasses elements of recognizable change, normative functioning, or failure to meet diagnostic criteria  for the treatment of ADHD in children and adolescents. Using these data, the present analyses (1) report similar results to a previous analysis by Goodman et al.  linking clinicaltrials.gov NCT03247530 . All participants were required to have a minimum ADHD-RS-5 total score of 28 at screening and baseline, and a minimum CGI-S score of 4 at screening. For any participant on ADHD medication before the study, drug washout was required for at least 1 week before randomization. An investigator/clinician trained in all scales administered the CGI-S at baseline only, the ADHD-RS-5 at baseline and each postbaseline study visit, and the CGI-I at each postbaseline study visit. The parent completed the WFIRS-P at the baseline and end of treatment or early termination visit (end of study [EOS]).Exclusion criteria included a current diagnosis of any major psychiatric disorders , major neurological disorders or history of seizure disorder within the immediate family, current evidence of significant systemic disease, evidence of suicidality within 6 months, body mass index >95th percentile for age and gender, history of receiving any investigational drug within the longer of 30 days or five half-lives before day 1 dosing of SPN-812, or any other reason which might have prevented the subject from participating in the study (as determined by the investigator). Participants were required to discontinue any ADHD medications at least 1 week before baseline/randomization and to refrain from taking any ADHD medications (other than the study medication) throughout the study until EOS.Eligible participants were randomized at baseline in a 1:1:1 ratio to either placebo or one of two doses of once-daily SPN-812 as follows: children (6–11 years of age) received either 100 or 200 mg in study P301 and either 200 or 400 mg in study P303; adolescents (12–17 years of age) received either 200 or 400 mg in study P302 or either 400 or 600 mg in study P304 . SubjectThe study protocol was approved by the Advarra Institutional Review Board (IRB) and conducted in accordance with the Helsinki Declaration and the International Council for Harmonization Note for Guidance on Good Clinical Practice. Parents or legal guardians provided written informed consent for all study procedures, including protocol amendments. All versions of the informed consent were reviewed and approved by the IRB.The CGI scales are two single-item, stand-alone assessments of a clinician's view of a patient's overall functioning that is nonspecific to any one disease, and are thus widely used in psychiatric evaluations  are rated on a 7-point Likert scale from 1  to 7 . CGI-S rankings from 1 to 7 are described as “normal, not at all ill,” “borderline mentally ill,” “mildly ill,” “moderately ill,” “markedly ill,” “severely ill,” and “among the most extremely ill.” CGI-I rankings from 1 to 7 are described as “very much improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” “much worse,” and “very much worse.”After an initial clinical evaluation, taking into account a patient's symptoms, behavior, and circumstances, an experienced rater can complete the CGI in typically less than a minute. Across each of the four studies evaluated here, the minimum score on the CGI-S for inclusion was 4 (“moderately ill”). Successful therapy is indicated by a lower overall score in subsequent testing. In each of the four trials, the CGI-S was administered at screening and baseline, and the CGI-I was administered at each weekly, postbaseline study visit, including EOS.The ADHD-RS is an ADHD-specific rating scale designed and validated to assess current ADHD symptomatology as described in the DSM-5, currently in its fifth edition (ADHD-RS-5), and is one of the most frequently used assessments in ADHD clinical trials  or Adolescent (P302/P304) instrument at screening, baseline, and at each weekly postbaseline study visit through to EOS. ADHD-RS-5 Total scores were used in the present analyses.The WFIRS-P assesses functional impairment in children and adolescents by quantifying the degree to which a patient's ADHD-related symptoms affect daily activities  over the past month . This technique identifies scores on both measures that have the same percentile rank, and has been used extensively in research on schizophrenia  in each of the four trials to (1) convert scores on each of the four scales  to percentile ranks using a percentile rank function, and (2) match scores on each scale that have the same percentile rank, and plot them as X, Y pair values. From this, a link function is generated for each matched scale, and, by using this function, scores on one scale can be translated into the other scale. This method links scores with the same percentile rank, regardless of which participant generated those scores, therefore, individual participant scores are not considered in the equipercentile linking analysis.Although scores on our scales are discrete, the equipercentile link function is continuous, thus, each score is expanded to encompass a range, for example, a CGI-S score of 4 (moderately ill) is represented here by any score 3.5–4.4, a score of 5 (markedly ill) is represented by 4.5–5.4, a score of 6 (severely ill) is represented by 5.5–6.4, and a score of 7 (extremely ill) is represented by 6.5–7. All scores are presumed to be uniformly distributed within the defined range, for example, all scores of 5 on the CGI-S are presumed to be uniformly distributed within the predefined 4.5–5.4 range. For each age group's link function, 95% confidence intervals (CIs) were calculated using a bootstrap imputation method, where data were imputed 200 times with replacement .Analyses were conducted on the intent-to-treat populations of all four trials, defined as all subjects randomized to treatment with both a baseline score and at least one postrandomization score on the CGI-I and at least one other assessment. The four clinical trials used as input to our analyses required minimum baseline scores of 28 on the ADHD-RS-5 and 4 on the CGI-S, with upward resulting ranges of 54 and 7, respectively. Eight subjects were inadvertently randomized despite having ADHD-RS-5 scores below 28: one child (score: 23) and seven adolescents (range of scores: 11–27). Thus, our link functions were based on data input from these ranges, and include subjects treated from 1 to 8 weeks, provided they had a baseline score and at least one postrandomization score as defined above.The endpoint of each assessment was defined as the last postrandomization treatment week for which a valid score was obtained , and only subjects with both baseline and EOS scores were included in each analysis. Across both assessments, the analysis was conducted on baseline scores, absolute CFB scores at EOS, and percent CFB scores at EOS.Analyses of baseline scores and treatment effects assessed by the CGI-I were conducted in GraphPad Prism . Link function analyses were conducted in SAS . To compare results from the present analyses with previously published analyses linking ADHD-RS-IV and CGI scores in children with ADHD treated with either placebo or lisdexamfetamine, we used Origin Pro  to extract data from the equipercentile link functions published in Goodman et al. . We plotThe study groups were balanced with regard to demographic characteristics. For children, the mean age was 8.5 years (standard deviation [SD] = 1.69). The majority of participants were male (63.8%), and 36.3% were female. Most participants were White (52.05%); 42.6% were Black or African American, 0.7% were American Indian or Alaska Native, 0.3% were Asian, and 4.3% were of multiple races. The majority of participants were Not Hispanic or Latino (72.0%), whereas 27.9% were Hispanic or Latino, and 0.1% were of unknown ethnicity. The mean height was 134.46 cm (SD = 11.30) and the mean weight was 31.63 kg (SD = 8.40).For adolescents, the mean age was 13.9 years (SD = 1.58). The majority of participants were male (65.6%), and 34.4% were female. Participants were predominantly White (61.4%); 34.2% were Black or African American, 0.8% were American Indian or Alaska Native, 0.3% were Asian, 0.2% were Native Hawaiian or Other Pacific Islander, and 3.0% were of multiple races. The majority of participants were Not Hispanic or Latino (68.5%), whereas 31.4% were Hispanic or Latino, and 0.2% were of unknown ethnicity. The mean height was 163.26 cm (SD = 10.36) and the mean weight was 57.27 kg (SD = 13.02).p-values <0.0001), no effect of study , no effect of assigned treatment group , and no two- or three-way interactions between these factors .To identify group differences at baseline, we performed three separate three-way analyses of variance of ADHD-RS-5, WFIRS-P, and CGI-S scores analyzing the effects of age (child vs. adolescents), study (first vs. second study), and assigned treatment group (placebo vs. SPN-812) on baseline scores. Each of the three analyses revealed a significant main effect of age  than adolescents, regardless of study or assigned treatment group . However, this effect is not likely to be clinically meaningful across each measure.p < 0.0001). Similarly, more children treated with SPN-812 (20.43%) were evaluated at EOS as very much improved  compared with children treated with placebo (11.90%) (p < 0.01).A two-sided Fisher's exact test compared the number of subjects treated with SPN-812 versus placebo achieving clinically meaningful improvements at EOS  . Signifip < 0.0001). Similarly, more adolescents treated with SPN-812 (24.17%) were evaluated as very much improved at EOS relative to adolescents treated with placebo (15.50%) (p < 0.05).Among adolescents, significantly more participants treated with SPN-812 (51.40%) were evaluated as much improved or very much improved at EOS compared with adolescents treated with placebo (32.50%)  linked with moderately ill, 44 (40–50) linked with markedly ill, and 52 (51–54) linked with severely or extremely ill. CGI-S levels corresponding with total ADHD-RS-5 scores based on this link function are described in The equipercentile link functions for absolute CFB ADHD-RS-5 and CGI-I levels in children and adolescents are shown in When considering the conventional measure for meaningful clinical improvement (much improved or very much improved combined), the median (range) of absolute CFB for children was linked with −30 (−16 to −54), and −26 (−16 to −52) for adolescents. CGI-I levels corresponding with the absolute CFB ADHD-RS-5 scores based on this link function are described in The equipercentile link functions for percent CFB ADHD-RS-5 scores and CGI-I levels in children and adolescents are shown in When considering the conventional measure for meaningful clinical improvement (much improved or very much improved combined), the median (range) of absolute CFB for children was linked with −70 (−38 to −100), and −69 (−44 to −100) for adolescents. CGI-I levels corresponding with the percent CFB ADHD-RS-5 scores based on this link function are described in To evaluate the reliability of these analyses, we overlaid the link functions generated in this study with those previously reported in children with ADHD treated with lisdexamfetamine or placebo linking the CGI scales with the ADHD-RS-IV  linked with moderately ill, 1.22 (0.94–1.62) linked with markedly ill, 1.83 (1.64–2.57) linked with severely ill, and 2.60 (2.57–2.86) linked with extremely ill. CGI-S levels corresponding with the WFIRS-P scores based on this link function are described in The equipercentile link functions for absolute CFB WFIRS-P scores and CGI-I levels in children and adolescents are shown in When considering the conventional measure for meaningful clinical improvement (much improved or very much improved combined), the median (range) of absolute CFB for children was linked with −0.66 (−0.32 to −2.46), and −0.52 (−0.20 to −1.95) for adolescents. CGI-I levels corresponding with the WFIRS-P scores based on this link function are described in The equipercentile link functions for percent CFB WFIRS-P scores and CGI-I levels in children and adolescents are shown in When considering the conventional measure for meaningful clinical improvement (much improved or very much improved combined), the median (range) of absolute CFB for children was linked with −61 (−35 to −100), and −52 (−27 to −100) for adolescents. CGI-I levels corresponding with the WFIRS-P scores based on this link function are described in post-hoc analyses are commonly used in clinical trials of ADHD to assess symptom severity (through the ADHD-RS-5) and functional impairment (through the WFIRS-P), two related yet separate constructs. The results presented here provide practical benchmarks for translating these scores into clinically meaningful benchmarks. These results should be useful for physicians seeking to understand a treatment's potential impact on their patients or for researchers looking to define the clinical relevance of their findings.The current analyses link scores on psychometrically validated assessments commonly used in clinical trials for ADHD with the clinician-preferred, clinically relevant CGI scales using data from four identical Phase 3 studies in children and adolescents with ADHD treated with either placebo or SPN-812. The assessments used in these While there is no standard definition for what constitutes clinically meaningful change after therapy, Jacobson and Truax  propose These standards align well with the present analyses, where we report a one-level change in CGI-I scores between the ranges of “no change” to “very much improved” to be associated with an absolute change in ADHD-RS-5 total scores of 10–15 points, or a percent change of 25%–30% , a rangeA separate report identified the WFIRS-P MID to be a 0.25 decrease in the total mean score  associate “minimally improved” with no clinically meaningful reduction of symptoms and very little change in functioning, whereas the CGI-I level “much improved” is described in terms of a significant reduction of symptoms and increase in functioning Kay . By thesp < 0.05), according to the present analyses an absolute CFB of 15 or fewer points is associated with minimal improvement on the CGI-I (The results described in this study and in a prior report (Goodman et al. he CGI-I , and as In the present analyses, the CGI-I level of much improved, generally understood to be the minimum level associated with clinically meaningful improvement, was associated with a score reduction from baseline of ∼55% on the ADHD-RS-5 , and 43%Taken together, these data suggest that the commonly used threshold of 30%, or the less frequently used, more stringent 40% threshold (Newcorn et al. Many researchers also assess clinically meaningful change through symptom normalization or remission, consistent with the twofold model proposed by Jacobson and Truax , frequenHowever, our data from the WFIRS-P show that a median WFIRS-P score of 0.64 is associated with the CGI-S level of moderately ill, defined in part by symptoms causing functional impairment that may warrant medication  Kay 199. This scAcross all six pairs of linkages, the relationship between the comprehensive assessments and CGI levels were generally consistent between children and adolescents, as measured by 95% CIs, with the exception of baseline ADHD-RS-5 scores  and WFIRAlthough the nonoverlapping CIs suggest these age differences are significant statistically, these differences are minor and are unlikely to be clinically meaningful. For instance, a CGI-S assessment of “markedly ill” was associated with an ADHD-RS-5 value of 47 in children, and 44 in adolescents , a diffeWhile the cause of these minor differences between child and adolescent link functions is unclear, it may reflect the nature of the assessments and changes in the clinical presentation of ADHD throughout development, which is well known to change across the lifespan (Wilens et al. The intuitive, impressionistic nature of the CGI might be more easily influenced by these easily observed, externalized symptoms of hyperactivity and impulsivity, providing for an impression of greater illness in children and opportunity to assess greater improvement in functional behavior, versus the more covert nature of inattention that is characteristic of ADHD in adolescence (Biederman et al. Whether the results reported in this study will extend to an adult population remain to be tested, although data from a trial of lisdexamfetamine (Goodman et al. post-hoc analyses and were not prespecified for these trials. When assessing percent CFB, because few participants experienced extreme levels of worsening, associations between scales in this region cannot be reliably interpreted, as indicated by the much wider CIs in the corresponding sections of Our results should be interpreted in the context of some limitations. These are These data are also from children and adolescents diagnosed with ADHD and do not include any healthy subjects, therefore precluding any conclusions about linking assessments within the normative ranges at baseline. While these analyses provide benchmarks for a evaluating a response to treatment relative to baseline per the CGI-I, they do not provide such benchmarks for the CGI-S at endpoint, thus precluding any conclusions about which ADHD-RS-5 or WFIRS-P scores are associated with remission after treatment. Although an ADHD-RS-5 score ≤18 and a WFIRS-P score of ≤0.65 are commonly used as thresholds of symptomatic and functional remission, respectively (Cutler et al. Finally, the utility of these results depends on a shared understanding of which CGI-I benchmarks and descriptors constitute clinically meaningful change (to this end, a comprehensive framework is described in Busner and Targum Clinical studies of ADHD typically use ratings of symptoms and impairments to evaluate participants. These measures may be unfamiliar to physicians or impractical for them to use during regular clinical treatment. Clinicians seeking to understand how much improvement scores on the ADHD-RS-5 or WFIRS-P are associated with clinically relevant treatment outcomes can use the present analyses as guidelines to inform treatment decisions. These analyses in children, and those of a previous report (Goodman et al.