Clinical characteristics and prognosis of early diagnosed Wilson's disease: A large cohort study.

BACKGROUND AND AIMS: Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure. METHODS: A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow-up over 1 year were analysed with Kaplan-Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes. RESULTS: Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 µg/24-h. There were 71 variants identified in the the copper-transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow-up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D-penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p < .01). CONCLUSIONS: Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome.

Co-occurrence of Spondyloepiphyseal Dysplasia and X-Linked Hypophosphatemia in a Three-Generation Chinese Family.

Rare genetic skeletal disorders (GSDs) remain the major problem in orthopedics and result in significant morbidity in patients, but the causes are highly diverse. Precise molecular diagnosis will benefit management and genetic counseling. This study aims to share the diagnostic experience on a three-generation Chinese family with co-occurrence of spondyloepiphyseal dysplasia (SED) and X-linked hypophosphatemia (XLH), and evaluate the therapeutic effects of two third-generation siblings. The proband, his younger brother, and mother presented with short stature, skeletal problems, and hypophosphatemia. His father, paternal grandfather, and aunt also manifested short stature and skeletal deformities. Whole exome sequencing (WES) of proband-brother-parents initially only found the proband and his younger brother had a pathogenic c.2833G > A(p.G945S) variant in the COL2A1 gene inherited from their father. Re-analysis of WES uncovered the proband and his younger brother also harbored a pathogenic ex.12 del variant in the PHEX gene transmitted from their mother. Sanger sequencing, agarose gel electrophoresis, and quantitative polymerase chain reaction proved these results. The proband and his younger brother were confirmed to have a paternally inherited SED and a maternally inherited XLH. During a 2.8-year follow-up, these two siblings remained short stature and hypophosphatemia, but their radiographic signs and serum bone alkaline phosphatase levels were improved with treatment of oral phosphate and calcitriol. Our study presents the first report of co-occurrence of SED and XLH, shows the possibility that two different rare GSDs co-exist in a single patient, and alerts clinicians and geneticists to be cautious about this condition. Our study also suggests that next-generation sequencing has limit in detecting exon-level large deletions.

Prevalence and risk factors of severe postpartum hemorrhage: a retrospective cohort study.

BACKGROUND: Although maternal deaths are rare in developed regions, the morbidity associated with severe postpartum hemorrhage (SPPH) remains a major problem. To determine the prevalence and risk factors of SPPH, we analyzed data of women who gave birth in Guangzhou Medical Centre for Critical Pregnant Women, which received a large quantity of critically ill obstetric patients who were transferred from other hospitals in Southern China. METHODS: In this study, we conducted a retrospective case-control study to determine the prevalence and risk factors for SPPH among a cohort of women who gave birth after 28 weeks of gestation between January 2015 and August 2019. SPPH was defined as an estimated blood loss ≥1000 mL and total blood transfusion≥4 units. Logistic regression analysis was used to identify independent risk factors for SPPH. RESULTS: SPPH was observed in 532 mothers (1.56%) among the total population of 34,178 mothers. Placenta-related problems (55.83%) were the major identified causes of SPPH, while uterine atony without associated retention of placental tissues accounted for 38.91%. The risk factors for SPPH were maternal age < 18 years (adjusted OR [aOR] = 11.52, 95% CI: 1.51-87.62), previous cesarean section (aOR = 2.57, 95% CI: 1.90-3.47), history of postpartum hemorrhage (aOR = 4.94, 95% CI: 2.63-9.29), conception through in vitro fertilization (aOR = 1.78, 95% CI: 1.31-2.43), pre-delivery anemia (aOR = 2.37, 95% CI: 1.88-3.00), stillbirth (aOR = 2.61, 95% CI: 1.02-6.69), prolonged labor (aOR = 5.24, 95% CI: 3.10-8.86), placenta previa (aOR = 9.75, 95% CI: 7.45-12.75), placenta abruption (aOR = 3.85, 95% CI: 1.91-7.76), placenta accrete spectrum (aOR = 8.00, 95% CI: 6.20-10.33), and macrosomia (aOR = 2.30, 95% CI: 1.38-3.83). CONCLUSION: Maternal age < 18 years, previous cesarean section, history of PPH, conception through IVF, pre-delivery anemia, stillbirth, prolonged labor, placenta previa, placental abruption, PAS, and macrosomia were risk factors for SPPH. Extra vigilance during the antenatal and peripartum periods is needed to identify women who have risk factors and enable early intervention to prevent SPPH.

Controllability on impulsive systems with delays in both input and impulse and its applications to multi-agent networks.

This paper investigates the controllability of impulsive systems with input delay and impulse delay and its applications in multi-agent networks. We adopt the geometric and algebraic analytical tools to establish some easily verified controllability conditions for the considered system model. First, the analytic solution of the considered system is established on every impulsive interval by using ordinary differential equation theory. Then, according to the solution derived, some sufficient complete controllability criteria are developed to reveal the role of the Gramian matrices in different subintervals. By introducing a row matrix of different kinds of Gramian matrices, a complete controllability condition that is proved to be necessary and sufficient is further obtained. By using the relevant geometric matrix theory, the derived algebraic controllability condition is then converted to a geometric one. On other hand, we introduce a multi-agent network with delayed input and impulse and investigate its controllability. By resorting to graph theory and matrix theory, several factors affecting the controllability of the considered multi-agent networks are investigated, such as the topology structure, the inner coupling matrix, and the dynamics of each agent. Finally, two numerical examples are worked out to verify the derived controllability criteria.

Fast synchronization control and application for encryption-decryption of coupled neural networks with intermittent random disturbance.

In this paper, we design a new class of coupled neural networks with stochastically intermittent disturbances, in which the perturbation mechanism is different from other existed random neural networks. It is significant to construct the new models, which can simulate a class of the real neural networks in the disturbed environment, and the fast synchronization control strategies are studied by an adjustable parameter α. A controller with coupling signal is designed to study the exponential synchronization problem, meanwhile, another effective controller with not only adjustable synchronization rate but also with infinite gain avoided is used to investigate the preset-time synchronization. The fast synchronization conditions have been obtained by Lyapunov stability principle, Laplacian matrix and some inequality techniques. A numerical example shows the effectiveness of the control schemes, and the different control factors for synchronization rate are given to discuss the control effect. In particular, the image encryption-decryption based on drive-response networks has been successfully applied.

Constructing Multiscroll Memristive Neural Network With Local Activity Memristor and Application in Image Encryption.

Memristor possesses synapse-like properties that can mimic excitation and inhibition between neurons. This article introduces the Sigmoid functions to the memristor and constructs a new memristive Hopfield neural network (HNN). Its most distinctive feature is the simple topology, which contains only unidirectional connections in neurons. The equilibrium points analysis reveals the mechanism of its multiscroll attractors generation. Homogeneous and heterogeneous coexisting attractors are observed with the variation of the network parameters. Note that the state equation of memristor can affect the number of coexisting attractors. A hardware implementation is designed for it, and the multiscroll attractors are captured in the oscilloscope. Finally, it is also applied to developing an image encryption algorithm with excellent performance.

Observer-Based Dynamic Event-Triggered Semiglobal Bipartite Consensus of Linear Multi-Agent Systems With Input Saturation.

Observer-based dynamic event-triggered semiglobal bipartite consensus (SGBC) is investigated for linear multi-agent systems (MASs) with input saturation under a competitive network. Based on the estimated relative information and low-gain feedback technology, distributed dynamic event-triggered control (DETC) protocols are proposed for solving the observer-based SGBC problems for MASs under a fixed topology and a jointly connected topology, respectively. It is turned out that the SGBC of MASs can be achieved under the proposed protocols. By using gauge transformation and the Lyapunov theory, the bipartite consensus conditions are obtained. Moreover, Zeno behaviors will be excluded. Finally, two simulation examples are presented to verify the theoretical results efficiently.

Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome.

Objective: Wiedemann-Steiner syndrome (WSS) is a rare autosomal dominant disorder caused by deleterious heterozygous variants of the KMT2A gene. This study aims to describe the phenotypic and genotypic features of Chinese WSS patients, and assess therapeutic effects of recombinant human growth hormone (rhGH). Methods: Eleven Chinese children with WSS were enrolled in our cohort. Their clinical, imaging, biochemical and molecular findings were analyzed retrospectively. Moreover, the phenotypic features of 41 previously reported Chinese WSS patients were reviewed and included in our analysis. Results: In our cohort, the 11 WSS patients presented with classic clinical manifestations, but with different frequencies. The most common clinical features were short stature (90.9%) and developmental delay (90.9%), followed by intellectual disability (72.7%). The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain. In the set comprising 52 Chinese WSS patients, the most common clinical and imaging manifestations were developmental delay (84.6%), intellectual disability (84.6%), short stature (80.8%) and delayed bone age (68.0%), respectively. Eleven different variants, including three known and eight novel variants, of the KMT2A gene were identified in our 11 WSS patients without a hotspot variant. Two patients were treated with rhGH and yielded satisfactory height gains, but one developed acceleration of bone age. Conclusion: Our study adds 11 new patients with WSS, reveals different clinical characteristics in Chinese WSS patients, and extends the mutational spectrum of the KMT2A gene. Our study also shares the therapeutic effects of rhGH in two WSS patients without GH deficiency.

Chaotification of complex networks with impulsive control.

This paper investigates the chaotification problem of complex dynamical networks (CDN) with impulsive control. Both the discrete and continuous cases are studied. The method is presented to drive all states of every node in CDN to chaos. The proposed impulsive control strategy is effective for both the originally stable and unstable CDN. The upper bound of the impulse intervals for originally stable networks is derived. Finally, the effectiveness of the theoretical results is verified by numerical examples.

Effect of Comprehensive Care Based on Appropriate Chinese Medicine Techniques on Urinary Retention and Bladder Function Recovery after Total Hysterectomy in Patients with Cervical Cancer.

Objective: To investigate the effect of comprehensive care based on appropriate Chinese medicine techniques on urinary retention and bladder function recovery after total hysterectomy in patients with cervical cancer. Methods: A total of 148 cases admitted after radical hysterectomy for cervical cancer from January 2019 to early September 2019 were used as the observation sample and were divided into control and experimental groups based on a randomized double-blind method. There were 74 cases each. The control group was given comprehensive care, and the experimental group was given comprehensive care based on appropriate Chinese medicine techniques. The intervention period was 2 weeks after surgery. The recovery rate of bladder function and the occurrence of urinary retention were compared between the two groups, and the duration of postoperative retention of urinary catheter, the amount of residual urine, and the feeling of urination were counted. Results: The experimental group had better urinary catheter retention time, time to first spontaneous voiding, time to get out of bed, and time to anal discharge than the control group; the experimental group had a higher rate of good bladder function recovery than the control group and better bladder recovery time, residual urine volume, and incidence of urinary retention than the control group; the patients in the experimental group had better UDI-6 scores. Conclusion: The implementation of comprehensive care based on appropriate Chinese medicine techniques can relieve patients' difficulty in urination and improve their quality of life.

Resilient Delayed Impulsive Control for Consensus of Multiagent Networks Subject to Malicious Agents.

Impulsive control is widely applied to achieve the consensus of multiagent networks (MANs). It is noticed that malicious agents may have adverse effects on the global behaviors, which, however, are not taken into account in the literature. In this study, a novel delayed impulsive control strategy based on sampled data is proposed to achieve the resilient consensus of MANs subject to malicious agents. It is worth pointing out that the proposed control strategy does not require any information on the number of malicious agents, which is usually required in the existing works on resilient consensus. Under appropriate control gains and sampling period, a necessary and sufficient graphic condition is derived to achieve the resilient consensus of the considered MAN. Finally, the effectiveness of the resilient delayed impulsive control is well demonstrated via simulation studies.

Multiagent Meta-Reinforcement Learning for Adaptive Multipath Routing Optimization.

In this article, we investigate the routing problem of packet networks through multiagent reinforcement learning (RL), which is a very challenging topic in distributed and autonomous networked systems. In specific, the routing problem is modeled as a networked multiagent partially observable Markov decision process (MDP). Since the MDP of a network node is not only affected by its neighboring nodes' policies but also the network traffic demand, it becomes a multitask learning problem. Inspired by recent success of RL and metalearning, we propose two novel model-free multiagent RL algorithms, named multiagent proximal policy optimization (MAPPO) and multiagent metaproximal policy optimization (meta-MAPPO), to optimize the network performances under fixed and time-varying traffic demand, respectively. A practicable distributed implementation framework is designed based on the separability of exploration and exploitation in training MAPPO. Compared with the existing routing optimization policies, our simulation results demonstrate the excellent performances of the proposed algorithms.

Neuroscience and Network Dynamics Toward Brain-Inspired Intelligence.

This article surveys the interdisciplinary research of neuroscience, network science, and dynamic systems, with emphasis on the emergence of brain-inspired intelligence. To replicate brain intelligence, a practical way is to reconstruct cortical networks with dynamic activities that nourish the brain functions, instead of using only artificial computing networks. The survey provides a complex network and spatiotemporal dynamics (abbr. network dynamics) perspective for understanding the brain and cortical networks and, furthermore, develops integrated approaches of neuroscience and network dynamics toward building brain-inspired intelligence with learning and resilience functions. Presented are fundamental concepts and principles of complex networks, neuroscience, and hybrid dynamic systems, as well as relevant studies about the brain and intelligence. Other promising research directions, such as brain science, data science, quantum information science, and machine behavior are also briefly discussed toward future applications.

Development and validation of a predictive model for severe postpartum hemorrhage in women undergoing vaginal delivery: A retrospective cohort study.

OBJECTIVE: To develop a predictive tool to accurately screen women at high risk of severe postpartum hemorrhage (SPPH) undergoing vaginal delivery. METHODS: We analyzed 28 150 mothers who underwent vaginal delivery after 28 weeks of pregnancy in the Third Affiliated Hospital of Guangzhou Medical University from January 2015 to August 2019. Two-thirds of the cohort were randomly allocated to a training set (n = 18 766) and the rest to a validation set (n = 9384). In the training set, we built a radiomic nomogram based on multivariate logistic analysis, and calibration and C-index were evaluated. The performance of the validated nomogram was then tested in the validation cohort. RESULTS: Independent risk factors for SPPH in women undergoing vaginal delivery were previous cesarean section, history of PPH, in vitro fertilization, anemia, intrauterine death, prolonged labor, low-lying placenta, placental abruption, placenta accreta spectrum, and macrosomia. Good calibration was observed for the probability of SPPH in the validation cohort, and the C-index of the nomogram for the prediction of SPPH was 0.861 (95% confidence interval 0.820-0.902). CONCLUSION: This model would be a useful tool to accurately screen for women at high-risk of SPPH undergoing vaginal delivery. It would be expected to be an effective tool to guide clinical practice and further reduce maternal mortality.

Clinical characteristics and long-term outcomes of 12 children with vitamin D-dependent rickets type 1A: A retrospective study.

Purpose: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by deficiency of the CYP27B1 gene. This study aims to investigate the phenotypic and genotypic features of VDDR1A children in southern China and evaluate the long-term therapeutic effects. Methods: Twelve children from southern China with VDDR1A were enrolled in this study. Their clinical, radiological, biochemical, and molecular findings were analyzed retrospectively. The rickets severity score (RSS), biochemical parameters, and height standard deviation score (HtSDS) were used to evaluate clinical outcomes. Results: Six males and six females were included in this VDDR1A cohort. The age of onset was from 6 months to 1.8 years, and the age at diagnosis was 2.1 ± 0.8 years. The most common clinical symptoms at diagnosis were delayed walking (10/12) and severe growth retardation (9/12). HtSDS at diagnosis was negatively associated with age (p < 0.05). All patients presented with hypocalcemia, hypophosphatemia, increased serum alkaline phosphatase and parathyroid hormone, and high RSS at diagnosis. Two allelic variants of the CYP27B1 gene were identified in all patients, including nine different variants, four known and five novel, with c.1319_1325dupCCCACCC(p.Phe443Profs*24) being the most frequent. All patients were treated with calcitriol and calcium after diagnosis, and all patients but one were followed-up from 6 months to 15.6 years. HtSDS, RSS, and biochemical parameters were found to be improved during the first few years of the treatment. However, only five patients had good compliance. Although RSS and biochemical parameters were significantly improved, the HtSDS change was not significant from the time of diagnosis to the last visit, and seven patients remained of a short stature (HtSDS < -2). Conclusion: Our study extends the mutational spectrum of VDDR1A and finds a hotspot variant of the CYP27B1 gene in southern China. The results reconfirm the importance of early diagnosis and treatment compliance and reveal the challenge of height improvement in VDDR1A patients.

Hybrid Neural Adaptive Control for Practical Tracking of Markovian Switching Networks.

While neural adaptive control is widely used for dealing with continuous- or discrete-time dynamical systems, less is known about its mechanism and performance in hybrid dynamical systems. This article develops analytical tools to investigate the neural adaptive tracking control of the hybrid Markovian switching networks with heterogeneous nonlinear dynamics and randomly switched topologies. A gradient-descent adaptation law built on neural networks (NNs) is presented for efficient distributed adaptive control. It is shown that the proposed control scheme can guarantee a stable closed-loop error system for any positive control gain and tuning gain. The tracking error is demonstrated to be practically uniformly exponentially stable with a threshold in the mean-square sense. This study further reveals how the topological structure affects the NN function, by measuring the influence of the switched topologies on the learning performance.

Consensus Tracking Control of Uncertain Multiagent Systems With Sampled Data and Time-Varying Delay.

In this article, the adaptive consensus tracking control is developed for uncertain multiagent systems with time-varying state delay in the case that leader's state is accessible at sampling instants. By proposing a distributed sampled observer with hybrid form, adaptive tracking controller with the complementary term is designed for first-order multiagent systems, and then is extended to high-order multiagent systems with the aid of dynamic surface control. Through the complementary term, the effects of parameter estimation error as well as dynamical terms with time-varying delays are eliminated and thus less conservative condition on time delays is required. It is proved that, under criteria in terms of linear matrix inequalities (LMIs), tracking error and estimation error exponentially converge to zero for first-order systems, and to a sufficiently small neighborhood of zero for high-order systems.

Effect of Rho GTPase activating protein 9 combined with preoperative ratio of platelet distribution width to platelet count on prognosis of patients with serous ovarian cancer.

BACKGROUND: This study aimed to investigate the relationship between Rho GTPase activating protein 9 (ARHGAP9) combined with preoperative ratio of platelet distribution width to platelet count (PDW/PLT) and patients prognosis with serous ovarian cancer. METHODS: The clinical data of 80 patients with serous ovarian cancer treated in Jiangsu Cancer Hospital from May 2011 to May 2016 were analyzed retrospectively. We verified ARHGAP9 expression in The Cancer Genome Atlas (TCGA) database, then detected messenger RNA (mRNA) expression encoding ARHGAP9 in ovarian cancer tissue samples using reverse transcription quantitative polymerase chain reaction (RT-qPCR). These patients were divided into an ARHGAP9 low-expression group and an ARHGAP9 high-expression group. The optimal critical value of PDW/PLT was determined by receiver operating characteristic (ROC) curve. The patients were divided into low PDW/PLT group and high PDW/PLT group. Kaplan-Meier method and log-rank test were used for univariate survival analysis, Cox regression method was used for multivariate analysis, and then a nomogram was constructed for internal verification. RESULTS: The ARHGAP9 protein was highly expressed both in TCGA serous ovarian cancer database and the serous ovarian cancer tumor tissues. There were significant differences in menstrual status, the International Federation of Gynecology and Obstetrics (FIGO) stage and grade between the ARHGAP9 low expression group and ARHGAP9 high expression group (all P<0.05). There were significant differences in FIGO stage, lymph node metastasis, and ascites between the low PDW/PLT group and high PDW/PLT group (all P<0.05). Finally, 80 patients were included, with a mortality rate of 45.0% and a survival rate of 55.0%; the median progression-free survival (PFS) was 19 months, and the median overall survival (OS) was 62.5 months. Cox multivariate analysis showed that PDW/PLT and ARHGAP9 were independent risk factors for tumor progression (P=0.026 and P=0.028, respectively). In the internal validation, the C-index of the nomogram was 0.6518 [95% confidence interval (CI): 0.5685 to 0.7352], and the prediction model had certain accuracy. CONCLUSIONS: ARHGAP9 and PDW/PLT Decrease can significantly prolong OS and PFS in serous ovarian cancer patients. Therefore, ARHGAP9 can be used as a new predictive biomarker and may be related to the immune infiltration of serous ovarian cancer.

Generating chaos for discrete time-delayed systems via impulsive control.

Generating chaos for a class of discrete time-delayed systems via impulsive control is investigated in this paper. With the augmented matrix method, the time-delay impulsive systems can be transformed into a new class of linear discrete impulsive systems. Based on the largest Lyapunov exponent and the boundedness of the systems, some theoretical results about the chaotification for the discrete impulsive systems with time delay are derived and an example is given to visualize the satisfactory control performance.

Distributed Control of Nonlinear Multiagent Systems With Unknown and Nonidentical Control Directions via Event-Triggered Communication.

In this paper, the leader-following output consensus problem for a class of uncertain nonlinear multiagent systems with unknown control directions is investigated. Each agent system has nonidentical dynamics and is subject to external disturbances and uncertain parameters. The agents are connected through a directed and jointly connected switching network. A novel two-layer distributed hierarchical control scheme is proposed. In the upper layer, to save the communication resources and to handle the switching networks, an event-triggered communication scheme is proposed, and a Zeno-free event-triggered mechanism is designed for each agent to generate the asynchronous triggering time instants. Furthermore, to avoid the continuous monitoring of the system states, a Zeno-free self-triggering algorithm is proposed. In the lower layer, to handle the unknown control directions problem and to achieve the output tracking of the local references generated in the upper layer, the Nussbaum-type function-based technique is combined with internal model principle. With the proposed two-layer distributed hierarchical controller, the leader-following output consensus is achieved. The obtained result is further extended to the formation control problem. Finally, three numerical examples are provided to demonstrate the effectiveness of the proposed theoretical results.