Microbial co-occurrence network analysis is being widely used for data exploration in plant microbiome research. Still, challenges lie in how well these microbial networks represent natural microbial communities and how well we can interpret and extract eco-evolutionary insights from the networks. Although many technical solutions have been proposed, in this perspective, we touch on the grave problem of kingdom-level bias in network representation and interpretation. We underscore the eco-evolutionary significance of using cross-kingdom  co-occurrence networks to increase the network’s representability of natural communities. To do so, we demonstrate how ecosystem-level interpretation of plant microbiome evolution changes with and without multi-kingdom analysis. Then, to overcome oversimplified interpretation of the networks stemming from the stereotypical dichotomy between bacteria and fungi, we recommend three avenues for ecological interpretation: (1) understanding dynamics and mechanisms of co-occurrence networks through generalized Lotka-Volterra and consumer-resource models, (2) finding alternative ecological explanations for individual negative and positive fungal-bacterial edges, and (3) connecting cross-kingdom networks to abiotic and biotic (host) environments. Plants are closely associated with microbes from diverse kingdoms, such as bacteria, archaea, protists, oomycetes, and fungi. Host health and its evolutionary trajectory are impacted by host–microbe interactions and the interactions among microbes from multiple kingdoms . In the Although co-occurrence network analysis has many unresolved intrinsic and technical limitations , it remaBy using cross-kingdom networks, researchers revealed that non-bacterial species can act as central hub species in a microbial community and that non-bacterial species can affect community stability and connectivity. We briefly summarize the literature first. Then, to further demonstrate the evolutionary significance of cross-kingdom networks in a plant-microbiome co-evolution context, we use a published rice seed microbiome network dataset.in silico extinction methods  were prevalent , connectance, transitivity, modularity, and nestedness. For the analysis, four co-occurrence networks were created for comparison: a bacterial-fungal network of wild rice, a bacteria-only network of wild rice, a bacterial-fungal network of domesticated rice, and a bacteria-only network of domesticated rice . NetworkThe addition of fungi alters bacterial node centrality in wild and domesticated rice. The addition of fungi boosted bacterial node centrality for most nodes of the wild rice network . In contin silico via extinction experiments. Nodes were deleted from the network in a given order: degree (highest to lowest), betweenness centrality (highest to lowest), eigenvector centrality (highest to lowest), and random deletion . Because the connectance of the random model had a standard deviation of 0, the Z-score normalization was done by dividing by the mean of the random model.Connectance, transitivity, modularity, and nestedness metrics were calculated in R or with the Vegan R package. To derive nestedness, only edges connecting bacterial and fungal species were used to create a bipartite network. Network robustness was examined to determine the effect of fungi on the stability of the microbial network. Robustness is a good measure of network stability when time-series data are not available to consider dynamics explicitly. Robustness curves revealed different effects in the attack order . If the Z-score normalized transitivity (clustering coefficient) and modularity (p = 0.019), but that of the domesticated rice network was not . Microbial community population dynamics can be modeled using the generalized Lotka-Volterra (gLV) model in the form:x(t) is a species abundance vector of length n containing the abundances of all species at time t, r is a vector of intrinsic growth rates in monoculture, and A is an n-by-n matrix of species-to-species interaction coefficients, thereby called community matrix. For example, Aij > 0 denotes that species i increases the abundance of species j, and Aji > 0 denotes species j increases species i’s abundance. D(x(t)) is a diagonal matrix with species abundance vector x on the diagonal. By constructing a gLV model, we can phenomenologically summarize the underlying ecology: biological growth (r) and species interaction type and strength (A). To infer these gLV parameters, regularized regression can be done with time-series sequence data with well-developed methods such as LIMIT  human stool time-series data . To our While the gLV model is phenomenological in explaining species interaction, the consumer-resource model can explain explicitly how resource densities influence consumer population growth rates and how in turn competing consumers affect their resources . A resouTo experimentally fit the consumer-resource model, time-series sequence (species abundance) data plus resource concentration (metabolite flux) data need to be collected. Recently, metabolite and species abundance dynamics were successfully predicted using a consumer-resource model in bacterial communities . With a A. thaliana  resource availability, (b) environmental stress, and (c) the host . RegardiZymoseptoria tritici indirectly altered bacterial species abundance by suppressing immune-related plant metabolism, making wheat vulnerable to further infection  grants funded by the Ministry of Science and ICT .KL and HK are grateful for a graduate fellowship from the Brain Korea 21 Plus Program.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.


Spinal and bulbar muscular atrophy (SBMA) is an X-linked, neuromuscular neurodegenerative disease for which there is no cure. The disease is characterized by a selective decrease in fast-muscle power  accompanied by a selective loss of fast-twitch muscle fibers. However, the relationship between neuromuscular junction (NMJ) pathology and fast-twitch motor unit vulnerability has yet to be explored. In this study, we used a cross-model comparison of two mouse models of SBMA to evaluate neuromuscular junction pathology, glycolytic-to-oxidative fiber-type switching, and cytoskeletal alterations in pre- and postsynaptic termini of tibialis anterior (TA), gastrocnemius, and soleus hindlimb muscles. We observed significantly increased NMJ and myofiber pathology in fast-twitch, glycolytic motor units of the TA and gastrocnemius compared to slow-twitch, oxidative motor units of the soleus, as seen by decreased pre- and post-synaptic membrane area, decreased pre- and post-synaptic membrane colocalization, increased acetylcholine receptor compactness, a decrease in endplate area and complexity, and deficits in neurofilament heavy chain. Our data also show evidence for metabolic dysregulation and myofiber atrophy that correlate with severity of NMJ pathology. We propose a model in which the dynamic communicative relationship between the motor neuron and muscle, along with the developmental subtype of the muscle, promotes motor unit subtype specific vulnerability, metabolic alterations, and NMJ pathology.The online version contains supplementary material available at 10.1186/s40478-022-01402-y. Ar) gene . Den. Den8]. To further understand a possible fast-to-slow fiber-type switch and the glycolytic-to-oxidative metabolic shift, we evaluated myosin heavy chain (MHC) isoform expression in soleus, TA, and gastrocnemius of both mouse models. Contrary to our hypothesis that gastrocnemius and TA muscles would exhibit a switch to increased expression of an oxidative, slow-type muscle MHC (MHC type I), gastrocnemius and TA showed a significant decrease in MHC I expression in both transgenic and knock-in muscle Fig. B, F. As Spinal and bulbar muscular atrophy (SBMA) is a debilitating neuromuscular neurodegenerative disease for which there is no cure . SymptomIn this study, our data revealed, as expected, that fast-twitch motor units of the gastrocnemius and TA showed more severe NMJ pathology than slow-twitch motor units of the soleus, and that this difference correlated with metabolic and structural changes in the innervated muscle fibers. However, our observations suggest a more complex interpretation than originally hypothesized, as NMJ pathology in the TA was limited to post-synaptic changes only in the transgenic model and was less severe than NMJ pathology in the gastrocnemius, even though both are considered fast-twitch muscles. One possible explanation for these observations is the developmental difference between gastrocnemius and TA in AChR clustering. It is known that, in response to disease and/or injury, both myofibers and motor neurons reinitiate the developmental program , 22, 78.Nefh and the subsequent alteration of the 4:1:1 neurofilament subunit ratio (NFL:NFM:NFH) has been shown to alter the structural integrity of neurofilaments, resulting in decreased axon caliber and decreased neuronal conduction velocity [NMJs in all three muscles evaluated in this study showed significant changes in NFH levels and/or distribution. NFH is one of four proteins that make up neurofilament, a cytoskeletal protein necessary for structural integrity and axon diameter . While ivelocity , 28, 76.velocity . The decvelocity  and at tvelocity , 59 mighThe NFH deficit seen in this study could result in decreased motor neuron conduction velocity, and therefore contribute to motor phenotypes. We considered carrying out electrophysiological studies to evaluate if motor neurons showing a decrease in NFH levels and/or distribution exhibited reduced conduction velocity, and to examine whether this correlated with glycolytic-to-oxidative fiber type switching seen in TA and gastrocnemius. However, stimulation and recording of the sciatic nerve would not allow for precise measurement of motor neurons innervating the muscles that have undergone fiber-type switching. To provide electrophysiological evidence for motor neurons innervating “switched” myofibers, motor neurons would need to be individually separated and evaluated for firing rate in vivo, which was beyond the scope of this study. Future studies using in vitro models of the neuromuscular junction could yield important information on motor neuron firing rate changes in SBMA models. In addition to its role in regulating axon diameter, NFH also has a role at the pre-synaptic terminal in determining the size of the readily releasable pool of synaptic vesicles and positioning organelles for energy needs , 76. ForWhile fragmentation has canonically been used to describe disease pathology at the NMJ , 63, we metabolic and cytoskeletal ‘fiber-type’ should be taken into consideration when evaluating neuromuscular disease, as the contractile properties of the myofiber may be discordant with its metabolic state. Previous studies have shown that mice defective in mitochondrial long chain fatty-acid synthesis showed alterations in mitochondrial metabolism that were discordant with myosin heavy chain expression [It is important to clarify that while muscle fibers show convincing evidence of a glycolytic-to-oxidative shift in metabolic state based on NADH-diaphorase staining, these data do not support changes in myosin heavy chain isotype expression in gastrocnemius or TA that would indicate ‘fiber-type switching’ at a cytoskeletal protein expression level. The distinction between pression . Coordinpression . Mef2 trpression . The evapression , along wpression , 62, conpression . Additiopression . Understpression , 32.In this study, we observed some differences between the two mouse models of SBMA. To understand the model-specific pathology, we considered that the mouse models used here differ in both age and polyglutamine-expanded AR expression. The transgenic model, which over-expresses polyglutamine-expanded AR primarily in the nervous system, showed no significant NMJ pathology at 6 months of age, despite significant motor deficits , 77. In en face NMJs, a random sample of NMJs was evaluated from each muscle. This random sample, combined with the heterogenous nature of the muscles evaluated, may have limited the power of this study to detect NMJ pathology in specific motor unit subtypes. However, while these data cannot provide insight on individual motor units, they do provide evidence to support increased vulnerability of muscles containing primarily fast-twitch myofibers in SBMA mouse models.A limitation of this study is the heterogenous nature of the muscles evaluated. While both gastrocnemius and TA represent “fast-twitch muscles”, they both contain a mixture of muscle fiber types that are known to change with age and anatomical location within the muscle , 25. BecOur model Fig.  proposesAdditional file1. Supplementary Methods. Supplementary Figs. 1–9. Supplementary Tables 1 and 2.


VA has several HCBS to offset caregiver burden, facilitate caregiving, and enhance Veterans’ home-based care, but they remain underutilized. We aimed to describe: the unmet psychosocial and HCBS needs of caregivers, barriers to accessing services, and gaps in available programs. Twenty-three caregivers participated in a 1-hr semi-structured interview . Caregivers provided 7.3 hrs of daily care ; most had provided care for 1+ year. Barriers to accessing HCBS included: a) disagreement with Veterans regarding service preferences and needs; b) lack of awareness of VA and non-VA programs; c) delays in obtaining services; and d) emotional toll of caregiving on personal health and relationship with the Veteran. The VA may need to invest in advertising existing services, develop strategies to match caregivers with available services when needed, and enhancing mental health and relationship quality for Veterans and caregivers.


Patient centeredness is an integral part of the quality of care. Patient-reported experience measures (PREMs) are assumed to be an appropriate tool to assess patient-centredness. An evaluation of German-speaking PREMs is lacking.To perform a systematic review and qualitative analysis of psychometric measurement qualities of German-language PREMs using for the first time a comprehensive framework of patient centredness.th November 2021) for studies describing generic, surgery- or cancer care-specific PREMs. All questionnaires that were developed in or translated into German were included. The content of the included PREMs was evaluated using a comprehensive framework of patient centredness covering 16 domains. Baseline data of all PREM studies were extracted by two independent reviewers. Psychometric measurement qualities of the PREMs were assessed using current COSMIN guidelines.A systematic literature search was performed in Medline, PsycInfo, CINHAL, Embase, Cochrane database  or translated into German (8 PREMs). Eight PREMs were generic , 4 cancer care-specific  and none was surgery-specific. None of the PREMs covered all domains of patient-centeredness. Overall rating of structural validity was adequate only for PEACS and HCAHPS. High ratings for internal consistency were given for NORPEQ, Schoenfelder et al., PSCC-G and the SCCC. Cross-cultural validity for translated questionnaires was adequate only for the PSCC-G, while reliability was adequately assessed only for the EORTC IN-PATSAT32. Due to a lack of measurement gold standard and minimal important change, criterion validity and measurement invariance could not be assessed for any of the PREMs.This is the first systematic review using a comprehensive framework of patient centredness and shows that none of the included PREMs, even those translated from other languages into German, cover all aspects of patient centredness. Furthermore, all included PREMS show deficits in the results or evaluation of psychometric measurement properties. Nonetheless, based on the results, the EORTC IN-PATSAT32 and PSCC-G can be recommended for use in cancer patients in the German-language region, while the German versions of the HCAHPS, NORPEQ, PPE-15 and PEACS can be recommended as generic PREMs.Registration. PROSPERO CRD42021276827. Improving the patient centredness (PC) of healthcare has been a main objective of healthcare politics over the last decades, including German-speaking countries , 2. PC hFurthermore, the dimensions of PC have not been clearly defined and several models have been proposed in the past . A systePatient-Reported Experience Measures (PREM) is most frequent as they permit a standardized appraisal of PC. PREMs aim to measure PC via the experience of patients in a certain healthcare context. Depending on this healthcare context four different categories of PREMs can be distinguished, although they partially overlap:Several methods have been proposed to measure PC in clinical practice . Assessmgeneric PREMs measure general aspects of PC and can be applied across multiple healthcare settings and disciplines.discipline-specific PREMs assess the PC within a certain discipline. For example, surgery-specific PREMs measure, among others, aspects of PC specific to surgical disciplines e.g. pain.healthcare pathway-specific PREMs measure the PC across a specific healthcare pathway. For example, a cancer care -specific PREM measures aspects of PC important to cancer patients irrespective of treatment  and healthcare setting .disease-specific PREMs aim to measure the PC of healthcare for patients with a specific disease, e.g., breast cancer.Patient-Reported Outcome Measures (PROM). PROMs measure medical outcomes, rather than dimensions of PC and therefore, address different domains of healthcare in the IOM quality of care model Studies containing PREMs that were not generic, surgery-specific or cancer healthcare pathway-specific. Therefore, disease-specific PREMs were excluded.The following information sources were searched:EBM Reviews—Cochrane Database of Systematic Reviews 2005 to November 9, 2021, EBM Reviews—Health Technology Assessment 4th Quarter 2016Embase 1980 to 2021 Week 40Ovid MEDLINE(R) ALL 1946 to November 9, 2021APA PsycInfo 1806 to November Week 2 2021CINHAL November 9, 2021th November 2021. An existing literature review on PREMs by Bull et al. was used as template . So. So34]. The study has several limitations. First, the search was limited to generic, surgery- and cancer care specific PREMs, i.e., PREMs for other disciplines  as well as PREMs for specific diseases were excluded. These PREMs can be found in the excluded fulltext list . AnotherAgency for Healthcare Research and Quality (AHRQ) (www.ahrq.gov/cahps/about-cahps/index.html) or the Swedish PREMs [A main finding of the study is the lack of psychometric data for many of the included PREMs. Frequently we were unable to find appropriate studies in accessible databases. However, many PREMs have been developed and are implemented by independent or commercial institutions or healthcare agencies. These institutions are often not scientifically driven and might not publish all available psychometric data. Exception are the transparent development and publication of data by the U.S. sh PREMs , 44, 45.If PC is supposed to be more than a declaration of intent of healthcare politicians, it will require the implementation of PREMs into everyday clinical practice via the following measures:As shown in our study, there is no comprehensive modular PREM system in the German language comparable to other countries . Many arThe missing psychometric properties of currently available German-language PREMs need to be evaluated.Most of the PREMs currently available are paper-based versions . For broIt is unclear which conclusions should be drawn from the results of PREM (sub)scales. If providers adapt their service based on PREM results, there is little evidence-base to guide such changes . IndividThere are two projects that should be mentioned in this context. First, the EORTC is currently developing and testing the PATSAT-33, a cancer-care specific PREM that will not only cover in-hospital patients, but also aspects of PC in out-patient settings as well as the transitional period . A phaseThis is the first systematic review using a comprehensive framework of patient centredness and shows that none of the included PREMs, even those translated from other languages into German, cover all aspects of patient centredness. Furthermore, all included PREMS show deficits in the results or evaluation of psychometric measurement properties. Nonetheless, based on the results, the EORTC IN-PATSAT32 and PSCC-G can be recommended for use in cancer patients in the German-language region, while the German versions of the HCAHPS, NORPEQ, PPE-15 and PEACS can be recommended as generic PREMs.S1 Fig(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableA) generic; B.) surgery-specific and C.) cancer care-specific PREMs.(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


Xu et al.), bacteria-based synergistic therapy , bioinspired membrane-coated nanoplatform , and injectable hydrogel delivery system , and so on.As an unprecedented approach, cancer immunotherapy has transformed cancer treatment. However, only a minority of patients benefits from cancer immunotherapy. In order to improve the efficacy of cancer immunotherapy and reduce the occurrence of immune-related adverse reactions, emerging engineering approaches have been explored for cancer immunotherapy. This invited Research Topic is composed of 16 articles, including 4 original research papers, 8 review articles, 1 minireview article, 1 opinion article, 1 perspective article and 1 case report, contributed by a total of 109 researchers from all over the world . This Research Topic covers a range of novel engineering approaches for cancer immunotherapy, including engineered T cells therapy . Traditional therapeutic includes surgery, chemotherapy, radiotherapy, etc. To seek better treatment strategies, it is crucial to understand the mechanism of tumor occurrence and development. Overexpressed NPM1 promotes tumor growth. Liu et al. analyzed TCGA and GEO data and found that NPM1 is a prognostic biomarker related to immune infiltration in lung adenocarcinoma (LUAD), and is related to m6A modification and glycolysis. As an effective target for the diagnosis and treatment of LUAD, this provides a new strategy for the therapy of LUAD. Histone acetylation plays a role in regulating tumorigenicity, tumor progression, and tumor microenvironment. Xu et al. comprehensively analyzed 36 histone acetylation regulators in hepatocellular carcinoma (HCC) for the first time, and found a close correlation between histone acetylation patterns and tumor malignant pathways and tumor microenvironment, which is an important indicator for hepatocytes and provides new strategies for personalized and precise immunotherapy and prognosis of cancer.Cancer has been threatening human beings with incurable, high mortality and high recurrence rate. Compared with non-tumor patients, tumor patients are more susceptible to SARA-Cov-2 and have poor prognosis . Combining traditional therapies with immunotherapy plays an important role in breast cancer . A case report has confirmed that combination of penpulimab and anlotinib can successfully treat extensive-stage small-cell lung cancer (ES-SCLC) . Engineered T-cell therapy includes adoptive T-cell therapy (ACT) , among which chimeric antigen receptor T Cells (CAR-T) therapy has received extensive attention, especially in hematological tumors. Nonetheless, engineered T-cell therapy faces many challenges that hinder its clinical application. To accelerate the development of ACT, suitable experimental models and test platforms can be selected. Xiao et al. demonstrated that immunocompetent microphysiological system (iMPS) could triple-culture three-dimensional (3D) colorectal tumor microtissues, 3D cardiac microtissues, and human-derived natural killer cells in the same microfluidic network, and was able to simulate the in vivo state for corresponding tests. This provides new approaches for efficacy and early safety testing of new candidate for ACTs. For a more economically desirable effect, regenerable human induced pluripotent stem cells (iPSCs) were genetically engineered to differentiate into immune cells with enhanced antitumor cytotoxicity, increased persistence and decreased immunogenicity. CAR-T cells derived from iPSCs can be pre-prepared as off-the-shelf products and applied in a large number of patients, offering great promise for the next generation of ACT . CAR-T therapy can create new complications such as cytokine release syndrome, neurotoxicity, and even fatal cerebral edema. CD28-CAR heterodimerization may be an important cause of severe neurotoxicity . To reduce its systemic toxicity, in vivo CAR-T cell therapy induced by gene editing tools can serve as a new generation of CAR-T cell therapy . The development of CAR-T therapy in solid tumors is still in its infancy. By adopting some nanotechnology, such as nanozymes, RNA vaccines, etc., to help CAR-T cells target and accumulate in solid tumors, or to stimulate CAR-T cells by remodeling the tumor microenvironment, improve the survival rate and proliferation rate of CAR-T cells, and provide new ideas for the application of CAR-T cells in solid tumors . Tissue resident memory CD8+ T (Trm) lymphocytes exist in various digestive tract cancers. CD8+ Trm cells own strong cytotoxicity, have ability to directly kill epithelial-derived tumor cells, and are important for maintaining the homeostasis of digestive tract mucosa and anti-tumor. But the application of CD8+ Trm cells in gastrointestinal cancers is still in its early stages. Specific drug therapy and cancer vaccine therapy targeting tumor-associated CD8+ Trm cells may become an important direction for precision cancer therapy .So far, immunotherapy has a place in cancer treatment, such as the application of immune checkpoint inhibitors for HCC . Bioinspired membrane-coated nanoplatform have opened up novel research directions for cancer immunotherapy due to superior immune regulation and excellent tumor targeting . The advantage of bacteria targeting tumor makes them an excellent platform for combination with immunotherapy. Optimizing bacteria-based therapy through strategies such as bioengineering or chemical modification can avoid the safety issues posed by this therapy .In addition to engineered T-cell therapy, other approaches have also been used to combat the challenges of cancer immunotherapy. Injectable hydrogel as a unique platform that can target the immunosuppressive tumor microenvironment have the advantages of good biocompatibility, good biodegradability and low toxicity (In general, this Research Topic reports the application of novel engineering approaches in cancer immunotherapy, which provides new ideas and strategies for cancer immunotherapy. Solving the challenges faced in cancer immunotherapy by various means has made an essential contribution to clinical translation and provides new hope for cancer patients.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The editors appreciate the contributions of all authors to this Research Topic, the constructive comments of all the reviewers, and the editorial support from Frontiers throughout the publication process. This work was supported by Collaborative Innovation Center of Suzhou Nano Science & Technology, the 111 Project.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.


Nonlinear differential equations rarely admit closed-form solutions, thus requiring numerical time-stepping algorithms to approximate solutions. Further, many systems characterized by multiscale physics exhibit dynamics over a vast range of timescales, making numerical integration expensive. In this work, we develop a hierarchy of deep neural network time-steppers to approximate the dynamical system flow map over a range of time-scales. The model is purely data-driven, enabling accurate and efficient numerical integration and forecasting. Similar ideas can be used to couple neural network-based models with classical numerical time-steppers. Our hierarchical time-stepping scheme provides advantages over current time-stepping algorithms, including (i) capturing a range of timescales, (ii) improved accuracy in comparison with leading neural network architectures, (iii) efficiency in long-time forecasting due to explicit training of slow time-scale dynamics, and (iv) a flexible framework that is parallelizable and may be integrated with standard numerical time-stepping algorithms. The method is demonstrated on numerous nonlinear dynamical systems, including the Van der Pol oscillator, the Lorenz system, the Kuramoto–Sivashinsky equation, and fluid flow pass a cylinder; audio and video signals are also explored. On the sequence generation examples, we benchmark our algorithm against state-of-the-art methods, such as LSTM, reservoir computing and clockwork RNN.This article is part of the theme issue ‘Data-driven prediction in dynamical systems’. In leveraging features at different timescales, we can produce an accurate and efficient computational scheme that can provide exceptional efficiency in long-time simulation/forecasting and that can be integrated with classical time-stepping algorithms.Scientific computing has revolutionized nearly every scientific discipline, allowing for the ability to model, simulate, engineer and optimize a complex system’s design and performance. This capability has been especially important in nonlinear, multiscale systems where recourse to analytic and perturbation methods are limited. For instance, modern high-fidelity simulations enable researchers to design aircraft, simulate the evolution of galaxies, quantify atmospheric and ocean interactions for weather forecasting, and model high-dimensional neuronal networks of the brain. Thus, given a set of governing equations, typically spatio-temporal omputing –3. Discromputing ,5. Time-straints –9. We bustraints ,10,11 inlocal in nature.Numerical discretization has been extensively studied since the earliest days of scientific computing. Numerical analysis has provided rigorous estimates of error bounds for the diversity of discretization schemes developed over the past few decades –3. Spatiflow map ,151.2x are natural candidates for temporal sequence modelling; however, training has proven to be especially difficult due to the notorious exploding/vanishing gradient problem [long short term memory (LSTM) algorithm [residual networks (ResNet) [Neural networks have been used to model dynamical systems for decades ,21. They problem ,63. To a problem –66, for lgorithm , or addi(ResNet) .residual network (ResNet) as the basic building block for modelling the flow-map dynamics To explore the effect of time step size on simulation performance, we consider the following simple linear differential equation for a harmonic oscillatorResults are plotted in  (b)For training data, we collect We follow  and empl (c)Multiscale modelling is ubiquitous in modern physics-based simulation models. Computational challenges arise in these simulations since coarse-grained macroscale models are usually not accurate enough and microscale models are too expensive to be used in practice . By coupCoupling neural network time-steppers across different time scales is rather straightforward, as shown in The proposed multiscale coupling procedure may resemble those used in multiscale simulations (e.g. HMM). However, the data-driven microscopic cannot provide accurate long-time forecasts on its own, so the coupling here is not only for efficiency but also to improve the long-time fidelity of the model. It should also be noted that before coupling neural network time-steppers across different time scales, cross validation is used to filter the models. This is practically helpful because qualities of different models may vary and we want to couple the best set of models. Specifically, suppose we have (i)The diagram for vectorized computations is illustrated in (ii)The flexibility of our multiscale coupling approach makes it possible to combine these time-steppers with classical numerical time-stepping algorithms. The algorithm is detailed in algorithm 2 and the concept is illustrated in . 3We will now provide a thorough exploration of our proposed multiscale hierarchical time-steppers. We begin by comparing against single time-scale neural network time-steppers and Runge–Kutta algorithms on simple dynamical systems. We then explore this approach on more sophisticated examples in spatio-temporal physics and sequence generation. (a)We first benchmark the multiscale neural network HiTS against the single time-scale neural network time-steppers on five simple nonlinear dynamical systems: a nonlinear system with a hyperbolic fixed point, a damped cubic oscillator, the Van der Pol oscillator, a Hopf normal form and the Lorenz system. For each example, we train 11 single time-scale neural network time-steppers with separate time steps, and then combine them into a multiscale neural network HiTS with the methods described in §c. More details about these numerical experiments can be found in electronic supplementary material, appendix A(a). —The model is trained with data from a single trajectory and then tested with the same initial state ,31. —The resulting model offers accurate short-term predictions while generating similar dynamical statistics for long times ,79. —The model predicts the Lorenz system with regular adjustments or intermittent external forcing or under a data assimilation framework ,80. By contrast, we train the model with batches of trajectories and test with unseen initial conditions; we also test long-term predictions without any external inputs. In fact, almost all previous models belong to single-scaled models in our discussion.a. Here, we report the The trade-off between computational accuracy and efficiency are visualized in figure 5ent with , which sb. In particular, we use a fourth-order Runge–Kutta integrator, with seven different sizes of uniform time step. For simplicity, the hybrid time-steppers are constructed from the same fourth-order Runge–Kutta (RK4) time-steppers with one large-scale neural network time-stepper at the highest level. More details can be found in electronic supplementary material, appendix A(b).Though the multiscale scheme improves the computational efficiency of neural network time-steppers, they still cannot easily match the efficiency of most classic numerical algorithms  for more details). Indeed, evaluating a neural network model (forward propagation) typically requires more computational effort than applying a classic discretization scheme that only involves a few evaluations of the known vector field. A hybrid time-stepper, on the other hand, may break this bottleneck by combining large-scale neural network time-steppers with classic numerical time-steppers to make the computations inherently parallelizable. Therefore, we benchmark the hybrid time-steppers against the classic numerical time-steppers in figure 5b shows the trade-off between accuracy and efficiency for our hybrid time-stepper and the classic RK4 scheme. Our hybrid time-stepper offers an efficiency gain over the Runge–Kutta time-stepper with the same minimal step size. This suggests the marginal benefits of enabling vectorized computation are potentially greater than the costs of evaluating a neural network time-stepper. But the accuracy of hybrid time-steppers are usually slightly lower than the purely numerical time-steppers with rare exceptions , as the global error is usually dominated by the error of neural network time-steppers, which are model agnostic and purely data-driven, limiting their ability to produce high-fidelity simulations.Figure 5 (b)sequence generation. Importantly, we benchmark our architecture against state-of-the-art networks, including long short-term memory networks (LSTMs) [In addition to integrating simple low-dimensional dynamical systems, here we show that it is possible to forecast the state of more complex, high-dimensional dynamical systems. In the field of machine learning, this is often termed  (LSTMs) , echo st (LSTMs) , and clo (LSTMs) ,82, and From In a nutshell, the competing architectures fail to capture the long-time behaviours, as error accumulation is inevitable for serialized computations. However, our proposed framework should not be viewed as a replacement for these state-of-the-art methods, as they take a different approach and philosophy for sequence generation. RNNs tend to uncover the full dynamics with the help of memory in their internal states, whereas our scheme performs reconstruction using the time-stepping schemes learned at different time scales, though these schemes may only be accurate for a few steps. Instead, our multiscale framework should be used to strengthen these existing approaches, as it can use data-driven models across different scales, avoiding local error accumulations and potentially boosting the accuracy and efficiency.. 4In this work, we have demonstrated an effective and general data-driven time-stepper framework based on synthesizing multiple deep neural networks for hierarchical time-steppers (HiTSs) trained at multiple temporal scales. Our approach outperforms neural networks trained at a single scale, providing an accurate and flexible approach for integrating nonlinear dynamical systems. We have carefully explored this multiscale HiTS approach on several illustrative dynamical systems as well as for a number of challenging high-dimensional problems in sequence generation. In the sequence generation examples, our approach outperforms state-of-the-art neural network architectures, including LSTMs, ESNs and CW-RNNs. Our method explicitly takes advantage of dynamics on different scales by learning flow-maps for those different scales. The coupled model still maintains computational efficiency thanks to the vectorized computations of array programming. Moreover, exactly due to this coupling scheme, each individual network can focus on their intrinsic ranges of interest, bypassing the exploding/vanishing gradient problem for training recurrent neural networks. In addition, we demonstrate the joint use of our neural network time-steppers with the classical time-steppers, resulting in a new computational paradigm: numerical simulation algorithms are now parallelizable rather than serialized in nature, leading to performance boosts in computational speed.This work highlights fundamental differences between physics-based simulation models and data-driven models. In the former, the errors of the time-stepping constraints are determined strictly by Taylor series expansions which are local in nature and limit the time-step a priori error bound using neural networks is rather involved compared to traditional time-stepping algorithms [However, some cautionary remarks are warranted: as with all DNN architectures, obtaining reliable large scaled time-steppers comes at the cost of significant training because of the increasing complexity ). Specifically, one usually needs to acquire large enough data sets to train the appropriate deep NN architecture. Deriving a rigorous gorithms . Derivingorithms ,85–87 maThis work also suggests a number of open questions that motivate further investigation. In particular, nearly every sub-field within numerical integration can be revisited from this perspective. For example, bringing the idea of adaptive step sizes into this framework may potentially lead to even more efficient and accurate time-stepping schemes. Although this important element may be naturally addressed, it is not yet built in to the proposed methodology in its present form. In addition, as mentioned in electronic supplementary material, appendix B(d), the increments of the flow maps mostly exhibit obvious multiscale features. Since deep learning is essentially an interpolation method , to leve


However, these results should be interpreted cautiously due to the limited number of included studies and varied sample population. In conclusion, the current review suggests that future intervention studies should incorporate self-esteem enhancement in the treatment of suicidal behaviors, especially for suicidal ideation.Suicide is a serious social issue and is often treated using psychological interventions. The current systematic review and meta-analysis aimed to investigate the effectiveness of self-esteem-related interventions on suicidal behaviors. A systematic literature search for randomized controlled trials (RCTs) including a self-esteem component was conducted on 29 May 2021 and updated on 4 April 2022. In total, 12 studies were included in the systematic review and five studies were included in the meta-analysis. Small effect sizes were found for suicidal ideation at post intervention [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=250882 Suicide is seen as a global phenomenon. The World Health Organization reported that approximately 800,000 suicide deaths occur per year, which means that one person dies by committing suicide every 40 s . SuicideA meta-analysis of RCTs from the last five decades revealed that while interventions were effective in reducing suicidal thoughts and behaviors, the effect size was small across all studies . This reOne possible mechanism for suicide is self-esteem. Low self-esteem is associated with negative mental health consequences and has been linked with 21 different disorders in the Diagnostic & Statistical Manual of Mental Disorders (DSM-5) as diagnostic criteria, associated features, risk factors or consequences . On the The relationship between self-esteem and suicide has been researched extensively in the past few decades. Low self-esteem has been identified as one of the most significant risk factors for suicide risk and suicidal behaviors –17. FurtSo far, only one meta-analysis has explored the relationship between self-esteem and suicide ; it repoIn summary, previous literature demonstrates that self-esteem is an important factor in the development of suicidal behaviors. Despite this evidence, the effectiveness of self-esteem-based interventions in prevention of suicidal behaviors remains unclear. Thus, the present review and meta-analysis aims to investigate whether treatment incorporating self-esteem enhancement is an efficacious approach to suicide prevention. This review distinguishes itself from previous reviews in several ways. First, we include only those studies that incorporate self-esteem as a treatment target in the intervention program, regardless of whether or not self-esteem is measured as an outcome. Thus, we call these types of interventions self-esteem-related interventions instead of self-esteem interventions like previous reviews. Second, the current review includes only those studies that have a suicidal outcome, such as suicidal ideation, suicide plan, or non-suicidal self-injury (NSSI). While NSSI and other suicidal behaviors are often differentiated, previous studies and theories have also shown that these two types of behaviors can often co-exist. For example, the role of NSSI is emphasized in Joiner's theory of suicide, which states that NSSI could directly increase an individual's acquired capability for suicide by making them accustomed to fear and pain .This review and meta-analysis have two aims:(1) To investigate the types of treatment or methods used to enhance self-esteem in suicide prevention.(2) To evaluate the effectiveness of interventions that incorporate self-esteem enhancement for reducing suicidal behaviors.This review and meta-analysis were conducted line with the PRISMA recommendations  for repo* or self-identit* or self-crit* or self-attack* or self-worth or self-efficacy or self-image) and (intervention* or program* or lesson* or treatment* or psychotherapy or psychoeducation) and (suicid*). These terms were searched in the PsycINFO, PubMed and Web of Science databases for publications from inception to 29 May 2021. In addition, the clinical trial register database  was searched to detect additional studies that had not yet been published. Similar reviews investigating the effectiveness of self-esteem interventions were also scanned for related studies. Finally, backward and forward reference searching was conducted using the included studies. In the PsycINFO and PubMed databases, Medical Subject Headings or MeSH terms were also added  Stated that one of the main targets is to enhance self-esteem (or related self-concepts)(b) Reported suicide-related outcomes. Suicide-related outcome here includes (1) suicidal ideation, defined as the thoughts about engaging in suicidal behaviors; (2) suicide attempt, defined as an act which leads to a non-fatal outcome but with an intention die; (3) suicide plan, defined as a serious planning about how one would kill oneself; and (4) NSSI, defined as the deliberate, self-inflicted destruction of body tissue without the intention of suicide(c) Used a randomized controlled trial (RCT) study design(d) Published in a peer-reviewed journal(e) Full text is available in EnglishStudies were excluded if they met any of the following criteria:(a) Were not intervention studies .(b) Did not include a self-esteem component in the intervention program(c) Did not report the assessment of a suicide-related outcome.(d) Did not follow an RCT study design.(e) Not published in a peer-reviewed journal (f) Full text is not available in EnglishThe following information was extracted from the articles to a spreadsheet: author names, year of publication, intervention design, duration, sample size, setting, diagnostic criteria, mean age and gender composition, country, co-morbidity, control group, number of participants in each group, outcome measures on suicidal behaviors, and outcome assessment timepoints. Data extraction was conducted by the first author and checked by the second author. When required data were unavailable, we emailed the corresponding author of the concerned article and requested access to missing data.Cochrane Collaboration's tool for assessing risk of bias in randomized trials  was usedThe included studies were synthesized and summarized narratively. Studies suitable for meta-analysis were included and analyzed using Review Manager .Meta-analysis was conducted to determine the effectiveness of interventions on suicidal outcomes. Standardized mean difference (SMD) was calculated due to the differences in the measurement scale. The SMD was calculated for post intervention and follow-up using Hedges' adjusted g. At post intervention, SMD was calculated for suicidal ideation. Follow-up data were sparse and varied in follow-up duration (ranging from 4 weeks to 6 months). However, four studies reported results for suicidal ideation at 3-month follow-up; thus, these data were also included in the meta-analysis. Meta-analysis was conducted using a random-effect model as opposed to a fixed-effect model because studies used a wide range of interventions and designs.I2 was calculated to assess for heterogeneity in treatment effects. According to Cochran's guideline (I2 can be interpreted as non-significant heterogeneity (0−40%); moderate heterogeneity (30−60%); substantial heterogeneity (50−90%) and considerable heterogeneity (75−100%).uideline , I2 can M = 100.35). One study  from four studies ; I2 = 5%, p = 0.38).A total of five comparisons . The meta-analysis at 3-month follow-up also yielded a small but significant effect size  at post-intervention from the current analysis was compared with similar meta-analysis involving other types of interventions. The results suggest that self-esteem-related interventions could be more effective than self-guided digital interventions  , as effeThe results revealed that the included studies used diverse intervention methods. Treatment ranged from CBT to writing intervention, with only three studies , 34, 39 It has been suggested that enhancing self-esteem is effective in the prevention of suicide, as high self-esteem could buffer the negative effects of many psychological risk factors for suicide . SpecifiA somewhat surprising finding from the current review is that the effect size for suicidal ideation at the 3-month follow-up was higher than at post-intervention. This result demonstrates that the effect on suicidal ideation caused by self-esteem-related interventions could be maintained even at follow-up. A possible explanation for this result is that the main goal of self-esteem programs is targeting and modifying self-critical thinking . Since sAlthough these results show a potential for self-esteem-related interventions in reducing suicide, they should be interpreted with caution due to several limitations. The numbers of included papers in this meta-analysis were small with a small sample size and varied sample population, which could lead to a high risk of bias. Different suicidal outcomes and follow-up periods also made it difficult to calculate the pooled effect size. Further, unlike previous studies , 24, 25,While self-esteem has been demonstrated to play a crucial role in mental health and well-being, self-esteem-based interventions remain nascent. As high self-esteem could protect against suicidality, it is possible that interventions for suicide may improve treatment efficacy by focusing exclusively on enhancing self-esteem or at least incorporate self-esteem enhancement as part of their treatment targets. Furthermore, while some self-esteem interventions or related psychological models currently exist  , 59, curIn summary, this is the first systematic review and meta-analysis on the effects of self-esteem-related interventions in reducing suicidal behaviors. The findings suggest that self-esteem-related interventions are effective in reducing suicidal ideation at post intervention and 3-month follow-up. However, due to the broad inclusion criteria and limited number of studies, these results should be interpreted with caution. Moderators such as intervention length, delivery method, and the contents of intervention should be investigated in future review. Finally, future studies should also assess the long-term benefits and mechanisms of change for each type of intervention.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Conceptualization: NM. Study design, literature searches, studies screening, and visualization: NM and ND. Data analysis and writing—original draft: ND. Writing—review and editing: ND, NM, YK, SA, YF, KTo, KTa, and IK. Supervision and final script validation: NM, YK, SA, YF, KTo, KTa, and IK. All authors contributed to the article and approved the submitted version.This study was supported by Japan Society for Promotion of Science (JSPS) KAKENHI (to SA) (Grant Number: JP 18K0758308).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.


This resource will allow exploration of these expression patterns, revealing important insights into cellular physiology and disease, and will aid with cell line selection and the interpretation of results when studying important cellular processes that depend on protein S-palmitoylation.The reversible lipid modification protein S-palmitoylation can dynamically modify the localization, diffusion, function, conformation and physical interactions of substrate proteins. Dysregulated S-palmitoylation is associated with a multitude of human diseases including brain and metabolic disorders, viral infection and cancer. However, the diverse expression patterns of the genes that regulate palmitoylation in the broad range of human cell types are currently unexplored, and their expression in commonly used cell lines that are the workhorse of basic and preclinical research are often overlooked when studying palmitoylation dependent processes. We therefore created CellPalmSeq ( S-palmitoylation is a reversible post-translational modification, in which the 16-carbon fatty acid, palmitate, is attached to a thiol group of specific cysteine residues via a labile thioester bond. As the most common form of S-acylation, this modification has profound influence over protein function and cellular signaling in the brain  and other purpose designed web resources. However, there are often barriers to easy access of this data, particularly when web resources for data viewing are not available.S-palmitoylation in the mouse brain, and demonstrated how these expression patterns can be used to better understand the etiology of diseases that are related to dysregulated S-palmitoylation, and to predict and validate enzyme-substrate interactions  to allow easy interrogation of this multi-study data using simple interactive heatmaps.A recent study from our lab collated and analyzed publicly available RNAseq data revealing considerable heterogeneity in the expression patterns of the genes that regulate ractions . HoweverS-palmitoylation, curated from multi-study RNAseq datasets from non-diseased human tissues, human cancer cell lines and commonly used non-human laboratory cell lines. We processed data for the 24 ZDHHC enzymes , the known ZDHHC accessory proteins . Therefore, we plotted individual heatmaps of ZDHHC expression within each cell-type cluster, with heatmaps scaled separately for each cell type cluster  data are available on CellPalmSeq to plot expression data according to user preferences.We first curated single-cell RNAseq data from the Human Protein Atlas, which analyzed collated data from 26 studies of cells from non-diseased human tissues and organs, identifying 76 broad single-cell types, divided into 15 cell type clusters  from which the cell lines were isolated, and plotted heatmaps that revealed highly heterogeneous expression of the genes that regulate S-palmitoylation across cancer cell lines for both the CCLE  between RNA and protein z-scores , a database repository of high throughput gene expression data, to manually curate available RNAseq data for the several of the most commonly used cell lines including: NIH/3T3, PC12, MDCK, BHK21, CHO, VeroE6, and Calu3 (https://ensembl.org) gene set for each species was used to extract the S-palmitoylation genes but as expected, not all genes we previously analyzed in human are identified in each species, therefore only those identified are included. All of these datasets are available for interactive visualization and download on CellPalmSeq.Numerous non-human cell lines are widely utilized in basic and pre-clinical research and have been used for the study of basic cell biology, drug toxicity, gene therapy and vaccine production . Howevernd Calu3 . We curaPubMed.gov. We found that expression patterns for the genes that regulate S-palmitoylation were very similar across four independent studies, particularly for the ZDHHC enzymes, despite the cell lines originating from three independent sources  are the most reliable resource for assessing relative trends in expression profiles of these genes.S-palmitoylation machinery in the human body and cell line model systems, and therefore will facilitate research into the role of S-palmitoylation in cellular biology and disease.CellPalmSeq will be an invaluable resource that will enable researchers and clinicians to easily interrogate the expression patterns of the www.proteinatlas.org/download/rna_single_cell_type.tsv.zip) were directly downloaded from (www.proteinatlas.org/about/download) and data were extracted (nTPM) for the genes that regulate S-palmitoylation.For Human Protein Atlas, normalized single-cell RNAseq data collated from 26 datasets  and averaged by cell lineage and primary disease. Proteomic data were downloaded from https://gygi.hms.harvard.edu/publications/ccle.html (file For Cancer Cell Line Encylclopedia (CCLE), RNAseq data were downloaded from https://cellmodelpassports.sanger.ac.uk/downloads  and averaged by tissue and cancer type.For Cell Model Passports (CMP), data were downloaded from https://ensembl.org. The RNAseq reads were downloaded from the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/), the series accession numbers and individual sample numbers are listed in For datasets downloaded from the GEO, the reference transcriptome of each species for which cell lines were analyzed from raw sequencing reads was acquired from All plots for the CellPalmSeq database were generated using curated RNA sequencing datasets. Python 3 and Javascript scripts were used with the plotting library Bokeh to generate the interactive heatmaps to display and compare these datasets on the CellPalmSeq website .https://www.displayr.com). Bar charts were plotted in GraphPad Prism 9.2.0 .Heatmaps within the manuscript were plotted in Displayr (


Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely employed to examine brain functional connectivity (FC) alterations in various neurological disorders. At present, various computational methods have been proposed to estimate connectivity strength between different brain regions, as the edge weight of FC networks. However, little is known about which model is more sensitive to Alzheimer's disease (AD) progression. This study comparatively characterized topological properties of rs-FC networks constructed with Pearson correlation (PC), dynamic time warping (DTW), and group information guided independent component analysis (GIG-ICA), aimed at investigating the sensitivity and effectivity of these methods in differentiating AD stages. A total of 54 subjects from Alzheimer's Disease Neuroimaging Initiative (ANDI) database, divided into healthy control (HC), mild cognition impairment (MCI), and AD groups, were included in this study. Network-level  and nodal (clustering coefficient) metrics were used to capture groupwise difference across HC, MCI, and AD groups. The results showed that almost no significant differences were found according to global efficiency and characteristic path length. However, in terms of clustering coefficient, 52 brain parcels sensitive to AD progression were identified in rs-FC networks built with GIG-ICA, much more than PC (6 parcels) and DTW (3 parcels). This indicates that GIG-ICA is more sensitive to AD progression than PC and DTW. The findings also confirmed that the AD-linked FC alterations mostly appeared in temporal, cingulate, and angular areas, which might contribute to clinical diagnosis of AD. Overall, this study provides insights into the topological properties of rs-FC networks over AD progression, suggesting that FC strength estimation of FC networks cannot be neglected in AD-related graph analysis. Alzheimer's disease (AD) is the most common cause for dementia, which has an insidious preclinical stage in which pathological tau accumulates slowly until clinical symptoms are observable in prodromal stages , 2. For Currently, many rs-fMRI studies have showed altered functional connectivity in AD –11. ThesAt present, dynamic FC patterns have been primarily investigated using sliding-window technique –21, indehttp://www.adni.loni.usc.edu). Detailed descriptions of the demographic and clinical features of the participants are provided in 3) and a 10-min resting-state fMRI . Participants were instructed to rest with eyes opened and stay awake in rs-fMRI scanning.Data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (The entire processing flowchart in this study is shown in https://web.conn-toolbox.org/) and SPM12  were used to perform T1-weighted MRI and rs-fMRI preprocessing, including spatial coregistration, functional realignment and unwarp, slice-timing correction, outlier identification, segmentation and normalization, and smoothing . Thmilarity . After Fmilarity , the firmilarity , 34.For topological analysis, we focused on global efficiency, characteristic path length, and clustering coefficient, which were calculated based on the estimated FC adjacency matrices using BCT toolbox . Our goaGlobal efficiency is inversely proportional to the average shortest path length. This metric measures how globally efficient a network is in the sense of connecting distant nodes together , 36. (1)dij is the shortest path length between node i and node j. N is the number of nodes in a network.where Characteristic path length indicates a lower capacity to integrate information using shortest path routing, revealing the integration of a network structure . (2)L=1Nti is the number of triangles around node and ki is the node degree.The clustering coefficient indicates the extent of local interconnectivity or cliquishness in a network. It is defined as the ratio of the number of triangles a given node belongs to over the total number of triangles it could belong to . (3)C=1Np value less than 0.05 (uncorrected) was considered statistically significant.Once the graph measures were extracted, we statistically evaluated groupwise difference. After whole-brain static and dynamic FC networks of each subject was built, groupwise differences of topologic metrics were assessed using one-way analysis of covariance (ANCOVA) tests with age and gender as covariates , 38. As As shown in 4At present, there are a few computational models to estimate FC strength between pairs of brain parcels, which were used to investigate FC alterations in various neurological disorders. In this study, we performed topological analyses on rs-FC networks of 18 HCs, 18 MCIs, and 18 Ads, aiming to finding a FC strength computational method sensitive to AD progression. Groupwise differences in global and nodal metrics were examined using ANCOVA tests with gender and age as covariates. Our results showed that almost no significant differences were observed across HC, MCI, and AD groups in terms of global metrics, and that much more affected brain regions by AD were revealed according clustering coefficient extracted from GIG-ICA dominant rs-FC networks. These findings provide new insights into understanding of the macroscopic network mechanisms underlying AD progression.p < 0.05, uncorrected) among HC, MCI, and AD groups were observed in terms of network-level metrics derived from rs-FC networks, including global efficiency and characteristic path length . By comparison, significant intergroup differences have been identified in structural connectivity (SC) networks [The human brain is a complex and interconnected network characterized by an efficient small-world network with high local clustering , 40. Comh length . In othenetworks , 41, 42.networks , 44. FC As a measure of local interconnectivity, clustering coefficient was estimated to examine FC disruption caused by AD. For rs-FC networks constructed with Pearson correlation and DTW, significant difference across HC, MCI, and AD groups were observed only in 6  and 3 T regions.Several limitations should be addressed in the future work. First, an empirically validated fixed sliding window of 20 TRs was selected in GIG-ICA. The selection of sliding window size is still inconclusive and may impact the evaluation of rs-FC connectivity strength. FC changes with separate windows of various window lengths will be evaluated in the future study. Second, the sample sizes included in the current study are relatively small, and the replication study with more participants needs to be performed in the future to verify our findings. Third, the whole brain was divided coarsely into 132 regions based on FSL Harvard-Oxford atlas and AAL template for functional brain network construction. Different parcellation strategies are required to validate our findings in future studies. Finally, the association between the disrupted brain functional networks and the neurological conditions was not explored. Future longitudinal studies are necessary to explore potential altered dynamic FC as a clinical biomarker.rs-FC has been often used to identify abnormal brain connectivity patterns in AD cohorts and to understand mechanisms of abnormal brain function, attempting to comprehensively explore the potential utility of rs-FC as a biomarker for AD progression. In summary, this study revealed that more affected regions can be significantly identified in terms of nodal clustering coefficient extracted from GIG-ICA dominant networks. As GIG-ICA dominant component was extracted from the concatenated time-varying rs-FC matrices, it may be concluded that dynamic FC analysis has the potential to provide more reliable and significant scientific findings than static FC studies. Our results also indicated the potential role of clustering coefficient in determination of early-stage AD patients, providing a clue to AD diagnosis and monitoring in clinical applications. In the next step, joint analysis between structural and functional networks could be a better way to reveal brain connectivity alterations over AD progression.


Second and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario.In this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases . Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata  software was used for the metanalysis.In total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups.Our analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule. Anaplastic lymphoma kinase (ALK) gene rearrangements have been found in up to 5% of non-small cell lung cancer (NSCLC) patients, mostly with adenocarcinoma histology, more frequently with young age and never- or light smoking history . ALK genThe development of ALK inhibitors (ALKIs) has dramatically changed the management of patients with NSCLC harboring this alteration. Crizotinib was the first-in-class molecule approved for clinical use in ALK-translocated lung adenocarcinoma . CrizotiAmong next-generation ALKIs, ceritinib has not been compared head-to-head to crizotinib, but standard chemotherapy, and only an adjusted indirect comparison with crizotinib is currently available , 9.Previous systematic reviews and meta-analyses of ALKIs for the treatment of NSCLC have highlighted improved OS and PFS of crizotinib and other ALKIs versus chemotherapy –12. NoneWe conducted a systematic literature review (SLR) following the Cochrane Handbook for Systematic Reviews for Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist , 17. As To describe the efficacy and safety of second and third-generation ALKIs as first-line treatment for patients with ALK translocated/rearranged NSCLC.Randomized phase III controlled trials including adults (≥ 18 years) with stage IV squamous or non-squamous NSCLC with ALK translocation/rearrangement and no prior chemotherapy or targeted therapy for stage IV disease were included. Interventions of interest included monotherapy with next-generation ALKIs, namely ceritinib, alectinib, brigatinib, lorlatinib, ensartinib.The systematic literature search was carried out in December 2021 on Embase, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR) databases. Additional sources included reference lists from relevant publications and congress abstracts (2010-2021) from the American Society of Clinical Oncology (ASCO), the European Lung Cancer Congress (ELCC), the European Society for Medical Oncology (ESMO), and the World Conference on Lung Cancer (WCLC) of the International Association for the Study of Lung Cancer (IASLC). Full search terms and the details of the databases interrogated are provided in two tables, see Outcomes of interest included: PFS , overall survival (OS), ORR, disease control rate (DCR), CNS response rate , and adverse events (AEs) .Two independent reviewers (EFG and GLB) screened titles and abstracts of retrieved records and then the full texts of potentially eligible papers, with discrepancies adjudicated by a third reviewer (AA). Detailed data extraction and risk of bias (ROB) assessment were carried out by two independent reviewers (EFG and GLB), with discrepancies adjudicated by a third reviewer (AA). ROB was assessed using the Cochrane Collaboration’s ROB tool for RCTs .Pooled hazard ratios (HRs) for time-to-event outcomes (OS and PFS), and risk ratios (RRs) for dichotomous outcomes , in both the experimental and controls arms, according to treatment type and in patients’ subgroups (only for PFS), were calculated. Regarding dichotomous outcomes and the RR calculation, studies not reporting the number of events were excluded from the analysis. A classic meta-analysis was conducted to estimate the experimental vs control arm pooled effect size for the time to event (pooled HR) and dichotomous outcomes (pooled RR). A minimum of two studies was required to proceed with data synthesis.2 coefficient and statistically tested by the Cochrane Q test.The study effect sizes were synthesized using random-effects models accounting for heterogeneity. Heterogeneity was quantified by the Higgins IP-values less than 0.05 were considered statistically significant. Stata  statistical software was used to compute.Our initial literature search found a total of 747 relevant citations from electronic databases and 202 congress abstracts. After the exclusion of duplicates, 501 studies were included. Subsequently, 494 of 501 studies were excluded because their abstracts did not fulfil our inclusion criteria Figure 1Seven trials met the eligibility criteria: ALEX, J-ALEX, ALTA-1L, ASCEND-4, ALESIA, eXalt3, and CROWN trial , 19–24. 2 = 65%, p for heterogeneity = 0.0142)   and DCR  were both higher with the next-generation ALKIs than controls, albeit with a different heterogeneity index  nor G≥3 AEs     , 22–24.  = 0.67) , 22–24.All the trials reported the AE-related drug discontinuation, five the dose reduction and four the dose interruption rates. There were non-significant differences between experimental and control arms for all those parameters Table 2 Overall, the trials were deemed at low risk for bias concerning blinding of outcome assessment  has relevant consequences on the interpretability of results, since the therapeutic sequence may profoundly influence OS –24, 29. Our meta-analysis did not identify any statistically significant difference between next-generation ALKIs and control therapies concerning safety data. However, it is noteworthy that each ALKI shows a different safety profile and specific AEs, with varying consequences on patients’ health. The higher dose reduction rates observed with next-generation ALKIs probably reflect the clinical need to find the appropriate drug dose for each patient, as it was not associated with an evident decrease in drug efficacy. We conclude that second and third-generation ALKIs do not demonstrate a worse toxicity profile than control therapies, but clinicians should consider that specific AEs in choosing among them.2 = 65%; p= 0.0142) could also be explained by the different trial follow-ups at the time of their analysis. The high heterogeneity observed in the ORR analysis  relies on the outlier value from the ASCEND-4 trial. This effect is likely related to the chemotherapy control arm and the corresponding lower disease responses than TKIs. G3-4 AEs analysis has also revealed a high heterogeneity , mainly driven by the three trials adopting alectinib as the experimental arm. Based on the forest plot, we could cautiously conclude for a more favorable safety profile of alectinib than all the other ALKIs. The heterogeneity in the dose interruption rate due to AEs , related to the low number of events registered in patients treated with alectinib, may be corroborated this hypothesis.Heterogeneity was found in the analysis of PFS, ORR, AEs, and dose interruption rate due to AEs, as reported in As alectinib, brigatinib, ceritinib, and lorlatinib have been approved as frontline therapy, and ensartinib is on the path to its approval, careful consideration of the individual patient characteristics could drive the choice of the appropriate first-line ALKI. Ceritinib, for instance, has been associated with gastrointestinal side effects, including diarrhea, vomiting, or elevated liver enzymes in the majority of patients. These effects can be managed by administering ceritinib with food . Alectinrd generation lorlatinib, its activity on acquired resistance mutations and the distinct safety profile, we would reserve lorlatinib for a subsequent line. While this consideration might crawl with the recommendation to use the most effective treatment upfront, we have to consider that tolerable and effective therapies are also essential for later lines of treatment. However, this field is continuously evolving with newer TKIs characterized by expanded activity like the TPX-0131 and NVL-655 currently under investigation and data on optimal sequencing likely be available shortly.Given the lack of head-to-head comparison between second-generation ALKIs and the 3Regarding other therapies for ALK-translocated lung cancer, data about immune checkpoint inhibitors (ICIs) are scarce and suggest inferior activity of single-agent ICIs (28a). When ALKIs fail, chemotherapy remains the standard of care, with the addition of ICI currently unclear as per the IMpower 150 trial and requiring further prospective data .There are several limitations related to our meta-analysis. First, we acknowledge the non-unique control therapy we considered . As noted above, we included the ASCEND-4, as ceritinib is a second-generation ALKI and crizotinib did not demonstrate an OS benefit over chemotherapy in the first-line setting. Another limitation is the exclusive enrollment of the Asian population in two trials, J-ALEX and ALESIA. Other limitations are the relatively immature OS data, the underreported data about serious and fatal events and the lack of individual patient data.Other meta-analyses have been published on the same topic –15. DiffThe recent approval of second and third-generation ALKIs has dramatically changed the treatment algorithm of ALK-translocated lung cancer. In the absence of head-to-head comparisons between next-generation ALKIs, any next-generation ALKI may be considered a valid option as first-line therapy , 34. OurThe original contributions presented in the study are included in the article/GB and AA: conceptualization and supervision; EG and AS: formal analysis, writing original draft, methodology; AS: software. HW, GM, AF, and KP: validation and review and editing. All authors contributed to the article and approved the submitted version.GB’s work was supported by “FPRC 5xmille Ministero Salute 2017 PTCRC-Intra 2020 ‘CTU-Lung’”.HW reports personal fees from Genentech/Roche, AstraZeneca, Merck, Takeda, and Bristol Myers Squibb; GM reports consultancies from Boehringer Ingelheim and Bristol-Myers Squibb and travel grants from AstraZeneca; AF reports personal fees from Roche, Pfizer, Astellas and Bristol Myers Squibb; GB reports personal fees from Janssen Cilag, Boehringer Ingelheim and Roche; AA reports personal fees from BMS, Astrazeneca, Roche, Pfizer, MSD, Boehringer;The remaining 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.


This study aimed to investigate the hypothesis that specific pattern of myocardial work (MW) distribution in patients with acute anterior ST-segment elevation myocardial infarction (STEMI) could provide prognostic value for predicting left ventricular (LV) remodeling.A total of 98 first anterior wall STEMI patients treated with primary percutaneous coronary intervention  were enrolled. Transthoracic echocardiography was performed 24–72 h after angioplasty and during 3-month follow-up. MW was estimated from the left ventricular pressure–strain loop derived from speckle tracking echocardiography and simultaneous noninvasive brachial artery cuff pressure. The primary endpoint was early LV remodeling, defined as an increase in LV end-diastolic volume ≥20% compared with baseline at 3 months after STEMI. Major adverse cardiac events and combined clinical outcomes were recorded.P < 0.0125). During follow-up, all global and regional WI, CW, and WE were improved (P < 0.0125 compared with baseline), with less improvement in patients with LV remodeling. In multivariate analysis, baseline delta-WE  and peak troponin I level  were independently associated with early LV remodeling. Patients with greater delta-WE at baseline were associated with a higher incidence of heart failure and combined clinical outcomes during follow-up.LV remodeling was present in 32 patients (33%), who exhibited lower global and culprit-regional work index (WI), constructive work (CW), work efficiency (WE), and specifically, greater differences of WE (delta-WE) and CW (delta-CW) between the culprit and non-culprit region than those without LV remodeling both at the acute phase and follow-up (all After reperfused acute anterior STEMI, patients with LV remodeling presented with more inhomogeneous MW distribution. The absolute difference of WE between culprit and non-culprit territory at the acute phase is an independent predictor for early LV remodeling.www.ClinicalTrials.gov, identifier: NCT05107102. Despite successful reperfusion therapy and widespread prescription of anti-remodeling medications, left ventricular (LV) remodeling remains a relatively frequent event after acute myocardial infarction (MI) . Acute mSeveral mechanisms have been proposed underlying the pathology of cardiac remodeling . Recent Patients with anterior ST-segment elevation myocardial infarction (STEMI) who underwent primary PCI < 12 h after symptom onset were consecutively enrolled in our center from September 2019 to May 2021. The diagnosis of acute anterior MI was based on chest pain lasting > 30 min, ST-segment elevation > 2 mm in at least two contiguous precordial electrocardiographic leads (from V1 to V6), and an increase in serum troponin I . In all All subjects underwent conventional two-dimensional echocardiography  at the acute phase (24–72 h after PCI) and at 3-month follow-up. Brachial pressure measurement was performed at the time of each examination. All echocardiographic examinations were performed by a senior cardiologist with subspecialty training in echocardiography. Apical two-, three-, and four-chamber views were stored at a frame rate of 50–70 Hz for offline analysis. Measurements were performed according to the recommended guidelines of the American Society of Echocardiography . RoutineThe LV global longitudinal strain (GLS) and MW indices were quantified using the vendor-specific module . GLS was measured using two-dimensional speckle tracking echocardiography by manually tracing the LV endocardial border. The LS values from each of the 17 LV segments from four-, two-, and three-apical views were averaged to calculate LV GLS.The MW was calculated as a function of time through a combination of LV GLS data and an estimated LV pressure curves . The peaThe values of culprit regional MW  and non-culprit regional MW  were obtained as the average of the segments belonging to the LAD or non-LAD territory  software . According to previous studies, the rate of LV remodeling after anterior MI was approximately 28–38% , 20, we t-tests for a nonnormal distribution and nonparametric tests, such as Mann–Whitney U test for a nonnormal distribution, were performed to assess differences in unpaired samples. Fisher's exact test was used for categorical data. To compare the changes in each group, paired t-tests or Wilcoxon tests were used. Logistic regression models were performed to test independent correlates of LV remodeling. Clinical characteristics and baseline echocardiographic parameters were included in the univariate analysis. To avoid the collinearity problems, age, sex, and variables with P < 0.05 in univariate analysis were included in a stepwise multivariate regression model (LR Forward). ROC curve analysis and Youden index were assessed to determine optimal cutoff points for sensitivity and specificity for identifying patients with LV remodeling. Intra- and interobserver variability of MW parameters was assessed using the intraclass correlation coefficient (ICC). A total of 20 subjects were randomly selected for that analysis. A two-tailed P < 0.05 was considered statistically significant. Furthermore, threshold level of significance for differences between groups was adjusted for multiple comparisons by Bonferroni's correction. The differences were statistically significant when the observed P-values were less than the specified significance level (α) divided by the number of tests (K) = 0.05/4.Statistical analysis was performed using SPSS  and MedCalc . The Kolmogorov–Smirnov test was used to examine the normality of distribution. Continuous variables were expressed as mean ± SD  or median and interquartile ranges . Categorical variables were expressed as percentages. To compare the values between patients with and without LV remodeling, independent P = 0.001) and BNP  level, as well as lower percentage of final TIMI 3 flow grades . For echocardiographic parameters, patients with LV remodeling exhibited reduced DTE , lower LVEF , higher WMSI , and significantly impaired LV GLS  than those without LV remodeling.A total of 116 patients with anterior MI were initially identified. Of them, 18 patients were further excluded: one patient had a history of pacemaker implantation, one patient had a history of mitral valve replacement, three patients had atrial fibrillation, two patients died during follow-up, four patients were not available for the follow-up at 3-month, and seven patients had poor echocardiographic quality images . A totalP = 0.002), GWE , and GCW  compared with those without LV remodeling. Similarly, significantly reduced regional WI-LAD , WE-LAD,  and CW-LAD  were observed in the LV remodeling group, while there was no difference for MW indices in the non-culprit territory between the two groups. Although the values of GWW  and WW-LAD  had an increased tendency in the LV remodeling group than the group without LV remodeling, there were no significant differences between the two groups. Of note, the difference of regional WE and regional CW between the culprit territory and the non-culprit territory at acute phase were higher in patients with LV remodeling compared with that in patients without LV remodeling, as indicated by higher delta-WE  and delta-CW . MW indices at the acute phase are presented in P < 0.0125). For regional MW indices, an improvement of regional WI, WE, and CW were presented not only in LAD territory but also in the non-LAD territory in patients with or without LV remodeling at follow-up compared with the acute phase . In contrast, no improvement of global or regional WW was observed . Of note, despite the recovery of MW, patients with LV remodeling still exhibited impaired global and culprit-regional MW indices (except GWW and WW-LAD), as well as greater delta-WE and delta-CW compared with patients without LV remodeling at follow-up .Evolution of MWs between the acute phase and 3-month follow-up is shown in P < 0.05 in the univariate regression  were included in a stepwise multivariate regression model (LR Forward), which identified that only TNI and delta-WE were independently associated with the incidence of early LV remodeling. Of note, each 1% increase in delta-WE was associated with a 2.30-fold increased risk of LV remodeling . The ROC analysis revealed a cutoff value of ≥15% for delta-WE to predict early LV remodeling with a sensitivity of 69% and specificity of 74% . There was no significant difference in the rate of cardiac death and reinfarction between the two subgroups   patients, including 2 (2%) cardiac death, 11 (11%) heart failure, and 1 (1%) reinfarction. There was no stroke occurred during follow-up. When the cutoff value of ≥15% for delta-WE was applied, we observed higher incidence of heart failure and combined clinical outcomes in patients with delta-WE ≥15% compared with those with delta-WE <15% (ctively) .Intra- and interobserver agreement was strong for both global and regional MW indices and is shown in The main findings of our study could be summarized as follows. (1) After an acute anterior MI, patients with early LV remodeling had more profound impairment of global and culprit-regional MW both at the acute phase and 3-month follow-up compared with those without LV remodeling. (2) During follow-up, MW indices (except for WW) were improved in both culprit and non-culprit region, with less improvement of MWs in patients with LV remodeling in comparison with those without remodeling. (3) Among MW indices at acute phase, the absolute difference of WE between culprit and non-culprit territory (delta-WE) was independently associated with the incidence of early LV remodeling, suggesting the imbalanced distribution of myocardial work efficiency after MI might serve as an independent predictor of LV remodeling.Several studies have investigated the alteration of MW in coronary heart disease. Compared with strain parameters derived from STE, MW assessment had exhibited higher sensitivity and specificity in identifying severe coronary stenosis or occlusion, as it took into account both myocardial deformation and the impact of afterload , 21. MeiConsistent with previous study , we obseCompared with patients without LV remodeling, patients with LV remodeling were associated with more profound impairment of global and culprit-regional MW at acute phase, along with higher TNI level, which may be associated with larger infarct size. Meanwhile, greater difference of WE between culprit and non-culprit territory was observed in patients with LV remodeling indicating a more inhomogeneous distribution of MW at the beginning of remodeling period, which was also observed in dyssynchronous hearts. Previous studies  in animaLV remodeling after acute MI is an important risk factor for the development of heart failure and all-cause mortality. Our study proposed a novel and noninvasive echocardiographic index, delta-WE for predicting early remodeling. Despite relatively small sample size and short follow-up period, we have observed that patients who exhibited greater delta-WE at the acute phase were associated with higher incidence of heart failure during 3-month follow-up, indicating that more intensive management and early preventive strategy should be implicated in this subset. Our findings suggested that delta-WE might serve as an indicator for stratification of prognosis at the acute phase of MI. Our result also implies that innovative therapies targeting myocardial metabolic processes   could beFirst, this study is a single-center experience with a relatively small sample, and the predictive value of MW indices needs to be further confirmed by validation group. Second, it was noted that the imbalance of MW distribution, especially in patients with LV remodeling, still persisted at the end of 3-month follow-up. Since the process of post-infarct LV remodeling may continue for up to 1 year or longer, the association between such uneven work distribution and late remodeling needs to be investigated by long-term follow-up. Third, the number of patients with LVEF recovery in our cohort was relatively small due to short follow-up period. Further study is needed to explore the predictive value of myocardial work indices for LVEF recovery.After reperfused acute anterior STEMI, patients with LV remodeling presented with more inhomogeneous MW distribution. The absolute difference of WE between culprit and non-culprit territory at the acute phase is an independent predictor for early LV remodeling.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 Ren Ji Hospital Ethics Committee + Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.HZ and X-dS conceived and designed the study. WW analyzed myocardial work data and executed the statistical analysis. WW, HZ, and FW acquired clinical data. WW and HZ drafted the manuscript. SD and JP amended the manuscript. All authors contributed to the interpretation of the data and approved the final version of this manuscript.This study was supported by the National Key Research and Development Program of China [2018YFC1312802]; the Shanghai Jiao Tong University School of Medicine (DLY201804); the Shanghai ShenKang Hospital Development Center (SHDC12019X12); and the Shanghai Municipal Key Clinical Specialty (shslczdzk06204).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.