In the context of Industry 4.0, the demand for the mass production of highly customized products will lead to complex products and an increasing demand for production system flexibility. Simply implementing lean production-based human-centered production or high automation to improve system flexibility is insufficient. Currently, lean automation (Jidoka) that utilizes cyber-physical systems (CPS) is considered a cost-efficient and effective approach for improving system flexibility under shrinking global economic conditions. Therefore, a smart lean automation engine enabled by CPS technologies (SLAE–CPS), which is based on an analysis of Jidoka functions and the smart capacity of CPS technologies, is proposed in this study to provide an integrated and standardized approach to design and implement a CPS-based smart Jidoka system. A set of comprehensive architecture and standardized key technologies should be presented to achieve the above-mentioned goal. Therefore, a distributed architecture that joins service-oriented architecture, agent, function block (FB), cloud, and Internet of things is proposed to support the flexible configuration, deployment, and performance of SLAE–CPS. Then, several standardized key techniques are proposed under this architecture. The first one is for converting heterogeneous physical data into uniform services for subsequent abnormality analysis and detection. The second one is a set of Jidoka scene rules, which is abstracted based on the analysis of the operator, machine, material, quality, and other factors in different time dimensions. These Jidoka rules can support executive FBs in performing different Jidoka functions. Finally, supported by the integrated and standardized approach of our proposed engine, a case study is conducted to verify the current research results. The proposed SLAE–CPS can serve as an important reference value for combining the benefits of innovative technology and proper methodology. TherefoWhen dealing with complex production tasks, human-centered systems cannot stabilize production and therefore suffer from inconsistent operations, defects, and other problems.Lean production aims to eliminate waste and effectively manage personnel such that each stage of production is done the best way possible. Therefore, lean production eliminates much of the creativity necessary for innovations , therebyHuman-centered systems: Among existing production management philosophies and methods, lean production focuses on human-centered production systems ,7. Lean (2)Automation systems: Automation systems are more stable than human-centered production systems in terms of operation efficiency, quality control, and other factors. Nowadays, robots, automated guided vehicles, automated warehouses, and other high-end automation equipment are widely used in factories to strengthen the said advantages. However, implementing new production systems is a systematic engineering process that integrates all aspects of enterprises. Simply applying high automation technologies to improve production system flexibility will cause problems, such as high investment costs, low investment returns, and investment transformation failure ,10,11,12(3)Lean automation: Whether companies can apply lean automation in a shrinking economy while focusing on innovations needed for survival is unclear . Lean auThe market globalization and diversification of customer demands have increased the mass production of highly customized products. Industry 4.0 is the fourth industrial revolution and describes the vision of a smart production system that meets market requirements using information communication technology (ICT), cyber-physical systems (CPS), Internet of things (IoT), and cloud computing . These mNowadays, Industry 4.0 technologies and the production flexibility demands can accelerate the development of Jidoka, broaden its contents, and make it smart. Industry 4.0 is propelled by CPS, which constructs a smart system by integrating advanced IoT, embedded control, and cloud computing technologies. This system covers mutual mapping, real-time interaction, and high-efficiency cooperation among man, machine, material, and information at physical and cyber levels; as a result, dynamic allocation of resources and running optimization of the system are enabled . CPS tecCPS-based Jidoka is a hybrid system  composed of diverse components, including analog and digital parts, actuators, controllers, ICT, software, and Jidoka rules. CPS-based Jidoka is distributed, such as network-embedded systems that can decouple centralized control and support distributed control. IoT has the power to achieve seamless connections, and each network-connected resource is easily controlled. Cloud technology can support remote and distributed applications. Therefore, a comprehensive architecture should be proposed to support the application of smart Jidoka before CPS-enabled Jidoka is studied. However, this area is yet to be explored.Under IoT, networks and protocols are heterogeneous and complex; thus, the data analysis and decision support capability of Jidoka are limited. Therefore, the second stage of CPS-based Jidoka application is converting heterogeneous network or protocols into uniform communication services. This issue is also not addressed by the related studies.IoT connects much resource to the production networks, thereby enabling the collection of various states of resources. This function allows Jidoka to detect abnormalities . However, existing research incomprehensively present production abnormalities.The potential of CPS has led to new fields of application for Jidoka. However, existing approaches are individualized solutions that are tailored to different needs. Thus, modularization and changeability are not supported.Although Jidoka has recently gained considerable attention in the context of Industry 4.0 ,18,19,20Therefore, a smart lean automation engine enabled by CPS technologies (SLAE-CPS) is proposed based on an analysis of Jidoka and the smart capacity of CPS technologies to address the above-mentioned research issues. This study aims to provide an integrated and standardized approach to design and implement a CPS-based smart Jidoka system. To achieve this goal, a set of comprehensive architecture and standardized key technologies are proposed based on service-oriented architecture (SOA), agent, function block (FB), cloud, and IoT. This CPS-enabled smart lean automation system is composed of sensors, actuators, controllers, ICT, software parts, and Jidoka rules, among others, and can autonomously convert heterogeneous data, analyze data, detect abnormalities, and control feedback. Compared with individualized solutions, SLAE–CPS is smarter and has a comprehensive architecture and standardized key technologies that support standardization, modularization, and changeability.The remainder of the paper is organized as follows. Architecture is described variously as an inherent aspect of systems or a description of the key characteristics of system composition, functionality, and behavior, and the rules and guidelines governing the design . A systeIndustry 4.0 architectures: The Zentralverband Elektrotechnik (ZVEI) of Germany defined the reference architectural model Industry 4.0 (RAMI 4.0) , which cIoT architectures: Gubbi et al. presented a cloud centric vision for worldwide implementation of IoT . D. Xu eCPS architectures: Lee and Bagheri proposed a five-level CPS structure , namely, the 5C architecture, and provided a guideline for developing and deploying a CPS for manufacturing application . Hu et aCPPS architectures: Jakovljevic et al. described the IEC-61499 which can be used for modeling a distributed CPPS. The scope of this standard is the reference architecture for utilization of FB for effective system integration in distributed control systems . Pérez eJidoka architectures: Jidoka is a functional production system that detects abnormalities and controls feedback. Therefore, a simple or incomplete functional architecture cannot support a standardized Jidoka application. As mentioned in This paper discusses four types of general architectures related to production systems: Industry 4.0, IoT, CPS, and cyber-physical production system (CPPS) architectures. The four general architectures can provide some guidelines for developing and deploying a smart Jidoka system. Given the functional difference in specific system architectures, related works only on Jidoka architectures are discussed.IoT enables CPS by connecting all distributed resources in the industrial environment to gain rich data and a deep knowledge of the environment; accordingly, operators and machines can perform complex tasks with fewer defects. For example, machine vision can be used for quality inspection, assembly verification, and device guidance . For theAgents are used to achieve distributed intelligence and adaptation for production systems ,31. FBs CPS needs to deal with the problem posed by heterogeneous networks and protocols when integrating components of different natures from different sources. Services can be positioned as higher-level abstractions to allow CPS to mediate the interactions among devices, software, information, humans, and applications within the existing technologies. Currently, SOA has been adopted in various industrial systems due to its integration flexibility and process composability ,35,36. IEach engineered system or component must be deployed to support performance. Currently, a large number of resources and services are allowed to deploy to different decentralized locations. Recently, the cloud emerged as a new way to develop and deploy sophisticated applications. Therefore, for supporting centralized and distributed implementations, a complete CPS may be specified as a single model composed of multiple components; the components may be executed or deployed at different locations locally and into the cloud . Cloud-bCPS architectures are the enabling technologies of Industry 4.0 and can make intelligent factories by bringing the virtual and physical worlds together to create a truly connected world in which intelligent objects communicate and interact with one another. CPS in an industrial environment can be regarded as cooperation systems that use cyber technologies embedded in and interacting with physical components that combine IoT, industrial agents, ubiquitous computation, cloud system, and SOA to make factories intelligent . Thus, tThe potential of CPS has facilitated the research and application of designing and integrating CPS into existing production systems ,42. For Lean production reduces factors that do not add value to focus on those that do. This management philosophy is derived mostly from the TPS and identified as “lean” only in the 1990s ,47. LeanIndividualized solutions for Jidoka: Danielsson et al. described a flexible lean automation concept for a robotized manufacturing industry . JacksonMOP methods: Individualized Jidoka solutions are supported by related MOP methods. For example, Berk et al. proposed a Jidoka quality control method that combines the conventional use of control charts and randomly occurring system stoppages for inspection or repair decisions . Gao et A production system consists of operators, machines, materials, products, the operation environment, and other resources. Therefore, the Jidoka function of abnormality detection is not limited to human–machine interactions, which have mainly been the focus of studies in the last decade. Nowadays, resources can be connected to the production networks, thereby enabling the collection of various states of resources. Therefore, corresponding monitoring–optimization–prediction (MOP) approaches may also be needed to support abnormality detection. MOP approaches are described as follows.Currently, CPS-based Jidoka is considered a cost-efficient and effective approach to improve system flexibility under the shrinking global economic conditions. According to existing studies, CPS can make Jidoka smart using IoT, SOA, agent, FB, semantics, and the cloud. The standardization, modularization, and changeability of Jidoka, which are critical for Industry 4.0, are not supported due to the lack of comprehensive architecture and standardized key technologies. Finally, MOP methods are effective and can be embedded in CPS-based Jidoka systems using of comprehensive architectures and standardized key technologies.SLAE–CPS consists of sensors, actuators, controllers, ICT, software parts, and Jidoka rules and can convert heterogeneous data, analyze data, detect abnormalities, and control feedback autonomously. The proposed SLAE–CPS structure is shown in (1)IoT-Pu): CPS presents a high combination and coordination between physical and computational elements. In CPS, physical and software components are deeply intertwined. In this study, physical elements are called IoT-Pu. In IoT-Pu can be classified into Identifying Unit (Idu), Information Unit (Iu), Actuators Unit (Au), and Controllers Unit (Cu).Idu: This part is responsible for addressing the sensing of normal assembly resources  by Iu. The general approach is to attach some identifying units  to the assembly resources. These identified resources can be sensed and recognized by some Iu . Therefore, based on the identified resources, some Iu can collect resource data and capture abnormal production data automatically.Iu: This part is responsible for perceiving (collecting) and transmitting production environmental data to Cu and activating corresponding SLAE–CPS scenes, such as scanning gun, RFID, machine vision, digital quantity and analog quantity sensor.Au: This part is responsible for executing Cu control commanders, responding to auto-stop commanders of SLAE–CPS Agent, and implementing corresponding logic actions  or logic control functions .Cu: This part is responsible for receiving cyber commands and controlling Idu, Iu, and Au to accomplish production tasks. Cu is composed of thing processing units with unified physical distributed logics , data storage, and logical judgment capability .IoT-Enabled Physical Unit ((2)AD-SLAECPS) and six FBs with different functions, namely, SLAE-mediator FB (SLAEM-FB), real-time data-triggered FB (RT-FB), time-event-triggered FB (TE-FB), trend prediction FB (TP-FB), warning and feedback control FB (WFD-FB), and offline management FB (OM-FB).AD-SLAECPS: As the core part of the SLAE–CPS agent, AD-SLAECPS is mainly responsible for downloading SLAE–CPS scene models into the local platform and into the C-PaaS platform and controlling six types of FBs to execute SLAE–CPS scene models under multiple modes . Meanwhile, AD-SLAECPS executes corresponding feedback control  functions according to abnormality grade. According to the practical requirements, the scene models can be configured as services, applications (web or desktop), or other types of executable models  bSLAEM-FB: This FB provides a service-call function that can acquire heterogeneous data, manage the connections among various types of networks through various industrial Ethernet protocols and communication technologies, and uniformize the heterogeneous data. Through this function, SLAEM-FB provides uniform CPS access to the SLAE–CPS agent.RT-FB: As one of the basic software FBs of the SLAE–CPS agent, RT-FB mainly executes the SLAE–CPS scene activation function under the real-time data triggering category. RT-FB registers the desired data request services according to scene configuration and triggers the corresponding SLAE–CPS scenes based on real-time data. Examples of these scenes include alarms when operating personnel enter a dangerous operation region, equipment alarms, and Andon alarms .TE-FB: This FB is one of the basic software FBs of the SLAE–CPS agent and mainly performs SLAE–CPS scene tests and time-event triggering. Embedded time and events in TE-FB cannot be triggered by real-time data and can only be triggered when the set threshold is met. Examples of this threshold include safety stocks for preventing store deficiencies, station timers for preventing imbalance in production lines, overall equipment efficiency, employee efficiency, and planned shut-down clocks.TP-FB: TP-FB combines historical running data of the system to analyze and mine potential abnormal factors in the production process that TE-FB and RT-FB fail to detect. As a basic software functional block of the SLAE–CPS agent, TP-FB analyzes abnormalities on the basis of mature data statistical analyses and mining algorithms and by setting knowledge rules to predict possible system anomalies and sending pre-alarms. These pre-alarms include those for quality anomaly decision rules based on statistical process control (SPC), curves based on mass historical data  for the predicted material delivery timing of the current production batch, and for fluctuations in operating personnel’s competency index. TP-FB can offer predictive device maintenance with a relatively mature failure prediction algorithm. In addition, TP-FB is the learning part of the SLAE–CPS agent and can make deep statistical analyses on abundant SLAE–CPS scene running data and produce new engine activation rules, such as statistics, updates in scene word frequency indexes, updates in SPC anomaly decision rules, and updates in competency index evaluation models. TP-FB can automatically update scene activation rules and trend prediction to some extent.WFD-FB: The SLAE–CPS agent is a cyber-physical agent integrated with a hardware module and software component. WFD–FB is the alarm and feedback control FB of the SLAE–CPS agent. This FB can control the built-in hardware module  of the SLAE–CPS agent and establish the feedback control communication channel with IoT-Pu through SLAEM-FB. WFD-FB executes alarm and control functions according to abnormality grade after receiving feedback commands from TE-FB, RT-FB, and TP-FB.OM-FB: This FB is the knowledge localization and offline data management part of the SLAE–CPS agent. To prevent SLAE–CPS agent failure caused by linkage interruption between the SLAE–CPS agent at the workshop’s upper and lower servers, OM-FB automatically updates the desired data and knowledge rules for the operation of the current SLAE–CPS agent regularly or after the SLAE–CPS agent is started. Moreover, OM-FB can offer offline storage of SLAE–CPS agent running data and transmission of SLAE–CPS agent running data to the server after communication restoration and updating of knowledge rules. As a result, completeness of global data and knowledge rules is ensured.SLAE–CPS Agent: The cyber-physical agent integrated with a hardware module and software component can access operating environmental data easily and execute poka-yoke (PY), anomaly detection (AD), trend forecast (TF), feedback (FED), and control and warning function (PY–AD–TF–FED function). An agent with independent communication, operation, and feedback control functions is called a SLAE–CPS agent. As an important component of the SLAE–CPS, the SLAE–CPS agent mainly consists of actuators for distributed SLAE–CPS scenarios ((3)SLAE Server: This server provides SLAE–CPS agent applications for enterprise knowledge rule storage, historical data storage, and model configuration and storage. Based on the certification of the C-PaaS platform, SLAE–CPS agent application models that are authorized and configured in the C-PaaS platform can be downloaded and updated.(4)C-PaaS: C-PaaS register functions are needed for SLAE–CPS agent applications for different types of customers and factories. A system supplier can perform SLAE–CPS agent application model configuration and deployment functions on the C-PaaS platform according to customer needs.SLAEM-FB and other FBs are explained in detail below.As the core component of SLAE–CPS, the SLAE–CPS agent is mainly composed of six FBs with different functions. Data in a production system can be collected from heterogeneous sources across different production system levels. These sources include different physical resources  and management information systems (MIS) , enterprise resource planning (ERP), product life cycle management (PLM), and product data management (PDM)). One of the first steps for production system management and control is to obtain heterogeneous data, and then uniformize and understand them. Some common Ethernet protocols , communication technologies , and various proprietary protocols  are developed to address the above-mentioned issues and integrate the data from heterogeneous hardware and software . HoweverAccording to the three types of communication modes, code development uses two modes: operation system-based device controller driver APIs (OS APIs) and web APIs . Three sSLAEM-FB that is independent of OS type and programming language  at the physical level and provide CPS access to other FBs or even cross-level ESB. The service-call mechanism is shown in SLAEM-FB first creates a constant communication link with the IoT-Pu base in the communication library (OS APIs and web APIs). Then, a corresponding semantic service will be generated and registered by AD-SLAECPS. Each physical address needs to be monitored and added to the semantic service. Finally, according to the real-time requirement of data acquisition and processing in the SLAE–CPS agent application, some data will be pushed to other FBs  immediately by the SLAEM–FB. Meanwhile, each cyber client can send requests to the SLAEM–FB and wait for a response. Therefore, this study proposes a service-oriented language . The SLASLAEM-FB is described as follows:SLAEM-FB handles various network connections and data acquisition and transformation. Therefore, each cross-platform cyber client does not need to know the physical-level data structure. A cyber client only needs to register and call a corresponding CPS service.SLAEM-FB can handle real-time updates through constant communication links. Therefore, according to the real-time requirement of data acquisition and processing in practical applications, data request and pushing mode are available.SLAEM-FB, TE-FB, RT-FB, TP-FB, and WFD-FB accomplish the PY–AD–TF–FED function of the SLAE–CPS agent by use of different types of real-time, time, event, and historical data. Jidoka scene parameters (JDKSPA) or Jidoka rules of PY–AD–TF–FED, which are needed in the SLAE–CPS agent, are analyzed and summarized from operators, equipment, material, and quality (OEMQ) in three time dimensions of RT-FB : Only one SLAE-MC is deployed in every production region or sub-production system. This module is used mainly to deploy Human Machine Interface (HMI) and Alarm Lamp (SLAE-HAL): This module receives the command of SLAE-MC and provides visual SLAE functions and human–computer interaction function for important production station.SLAE Andon Box (SLAE-ABOX): This module receives the command of SLAE-MC and provides relatively important stations of different types of production indication and anomaly alarm by combining different colors of indicator light and alarm light. Operators can trigger different types of SLAE-ABOX buttons manually according to the abnormality of station to execute corresponding Andon functions.Wireless Alarm Lamp (SLAE-WAL): This module receives the command of SLAE-MC and provides the most basic SLAE indication and alarm to stations with few production indications and anomaly alarm.The developmental and experimental environment is shown in The piston rod assembly region in the engine assembly line of an automobile enterprise is shown in This project was implemented in 2012. As shown in The above-mentioned description is combined with the topological structure shown in Compared with individualized solutions, SLAE–CPS presents a comprehensive architecture that joins SOA, agent, FB, cloud, and IoT to support flexible configuration, deployment, and smart performance of Jidoka systems.A standardized key technology for converting heterogeneous network or protocols into uniform communication services for a deep and varied abnormality analysis and detection is proposed to strengthen the data analysis and decision support capability of Jidoka.In the context of Industry 4.0, IoT can enable a collection of various states of resources. Thus, comprehensive Jidoka scene parameters (or Jidoka rules library) are necessary and useful for a flexible configuration and performance of Jidoka systems.Following the comprehensive and standardized approach of SLAE–CPS, a case study is conducted to demonstrate the practicality of the proposed SLAE–CPS. The advantages of SLAE–CPS are further illustrated by a comparison between integrated Jidoka and SLAE–CPS .CPS-based smart Jidoka is considered a cost-efficient and effective approach for improving production system flexibility under a shrinking global economy. SLAE–CPS and its architecture and key technologies are discussed and developed in this study. Compared with individualized solutions, the proposed SLAE–CPS is generally smarter and has more comprehensive architecture and standardized key technologies that support system standardization, changeability, and modularization. The contributions of this study are discussed as follows.New SLAE–CPS tools based on C-PaaS should be developed to achieve agile implementation and remote data analysis.The design should be implemented with security protocols to fully benefit from the many application of CPS. Therefore, the overall security mechanism for SLAE–CPS should be considered, such as sensing security, communication security, actuation control security, and feedback security.Although the SLAE–CPS tools have been verified in laboratory, system stability needs to be further tested.New mature embedded technologies and human–machine interaction technologies  should be used to create a smart SLAE–CPS.The advantages of the proposed SLAE–CPS are verified by the case study; however, some challenges, which will be addressed in the future research, still need to be overcome.


Background: Accumulating evidence indicates that cognitive remediation (CR) is effective for improving various cognitive deficits in adult patients with schizophrenia. Although reports of brain plasticity in older adults and the service needs for chronic patients with schizophrenia are increasing, very few randomized controlled trials of CR have been conducted in middle-aged or older inpatients with chronic schizophrenia. We investigated the efficacy of individualized CR on the cognitive impairments of middle-aged or older inpatients with chronic schizophrenia within the context of comprehensive psychiatric rehabilitation (PR) by comparing the results obtained with PR only and treatment as usual (TAU).Method: Fifty-seven middle-aged and older individuals with chronic schizophrenia and mild to moderate cognitive deficits were enrolled. Thirty-eight who were undergoing PR were randomly assigned to CR + PR (N = 19) or PR-only (N = 19) groups. Nineteen participants who were undergoing TAU without CR or PR were evaluated pre- and post-treatment.Results: CR was easily provided and well received (drop-out rates = 5.3%) by middle-aged or older psychiatric inpatients. Compared to the PR-Only or TAU patients, patients in the CR + PR group showed greater improvement in executive functioning. Compared to TAU patients, CR + PR and PR-only patients showed greater improvement in logical memory. More patients in the CR + PR group improved clinically significantly in executive functioning and logical memory, compared with the PR-only and TAU patients.Conclusions: These results suggested that CR improved some cognitive deficits in middle-aged or older inpatients with chronic schizophrenia and that it was effective as an adjunctive treatment to the usual PR services provided in inpatient settings.Clinical Registration: KCT0002609 Cognitive deficits have been identified as a key predictor of the functioning of patients with schizophrenia across various phases of the illness from the first episode to chronic illness, even after considering the patients' psychiatric symptoms Green, . CognitiGiven the therapeutic and functional importance of cognitive deficits in this population , and it reported null effects in the neuropsychological assessments of the outpatients compared to active control groups  group (without PR) as another control group. Importantly, to the best of our knowledge, no RCTs have been conducted on non-western inpatients within the context of comprehensive PR, even though inpatient clinics, in conjunction with community-based PR, are important settings for PR.Thus, in the current study, we employed a RCT design (CR + PR vs. PR only) to evaluate the efficacy of a CR program for middle-aged or older inpatients with chronic schizophrenia within a PR context compared to TAU. We hypothesized that CR + PR treatment would result in the greatest improvements, followed by PR only and TAU, in untrained neurocognitive domains and psychiatric symptoms in middle-aged or older inpatients with chronic schizophrenia.Of the 79 inpatients with schizophrenia who were referred to this clinical trial (53 from the PR unit and 26 from the TAU unit), eight did not meet the inclusion criteria and 14 declined to participate. A final total of 38 inpatients with schizophrenia from the PR unit who met the inclusion criteria of the study and who gave consent were randomly assigned to the CR + PR or PR-only groups  were confirmed by the Structured Clinical Interview for DSM-IV Axis I disorders  , Wisconsin Card Sorting Test (WCST) 64, and Verbal Fluency Test. The Trails B requires the examinee to draw a line between numbers and letters that are scattered on paper following the given rules within 360 s  was translated in Korean by K. H. Choi's research group and then used for CR training Bracy, . The CR The participants who were randomized to the CR + PR and PR-only groups received comprehensive inpatient PR, including optimal pharmacotherapy, vocational rehabilitation, social skills training, daily living skills training, illness management, independent living skills training, and patient empowerment program. The PR did not include specific training on neurocognitive functioning.The participants who were recruited from the TAU unit received optimal pharmacotherapy, psychoeducation, socialization and recreational programs. The TAU group did not receive specific training on neurocognitive functioning or PR-specific components, such as vocational rehabilitation or skills training.Post-hoc analyses were conducted to compare the group means at each time point. To estimate the clinical significance, the reliable change index (RCI) was calculated and compared among the groups . RCI scores that were equal or >1.96 are considered reliable changes ] were conducted to examine the effects of CR on the neurocognitive measures, psychiatric symptoms, and clinic unit behaviors. The effect sizes were calculated with the Time-by-Group interaction. ps Wise, . The RCIes Wise, .*Power    to investigate whether the groups differed at post-treatment , while the CR + PR and PR-only groups did not differ in both LM I and II. The PR-only group showed greater performance at a trend level of significance compared with the TAU group .Least Significant Difference p = 0.026; WCST %CL: mean difference = 16.47, p = 0.017) and TAU group . However, no group differences were found on WCST total errors and WCST %CL between the PR-only and TAU groups  Table .2 = 8.35, p = 0.02; LM II: χ2 = 6.92, p = 0.03). Differences with trend levels of significance were found for WCST total errors  and WCST %CL  .The RCIs were calculated for LM I and II, WCST total errors, and WCST %CL, which showed significant time × group interactions. As recommended by Wise Wise, , RCI scoThe current study aimed to investigate whether CR treatment within the context of PR treatment (CR + PR) would produce meaningful improvements in neurocognition and psychiatric symptoms in middle-aged or older inpatients with chronic schizophrenia compared to either the PR-only or TAU group. For the CR, we employed a highly personalized and computerized CR protocol with motivational enhancements through a bridging group and motivational interviewing. To the best of our knowledge, the current study is the first RCT of middle-aged or older inpatients with chronic schizophrenia compared with PR-only and TAU groups, especially conducted in a non-western country.The results of the current study partially supported our primary hypothesis. Specifically, compared with the PR-only and TAU groups, the CR + PR group showed greater improvement in executive functioning . In addition, the CR + PR group showed greater improvements in immediate and delayed LM compared with the TAU group but not the PR-only group. The PR-only group also showed greater improvements in immediate and delayed LM compared with the TAU group. The PR group improved more in executive functioning than the TAU did, but the difference was not reach significant. Importantly, the RCIs indicated that more participants in the CR + PR group had clinically meaningful improvements in LM and executive functioning compared with participants in the PR-only and TAU groups. However, since TAU group was not randomly assigned, the differences between “CR+PR vs. TAU” or “PR-only vs. TAU” should not be interpreted as causation.These findings suggest that CR has additional treatment benefits for executive-level operation when it is delivered within a larger context of PR compared with PR only. Inpatient PR has nonspecific treatment effects on neuropsychological functioning, even without explicit CR training  and older outpatients (longer-course group) with schizophrenia improved in working memory (digit sequencing) and executive functioning (Tower of London), but only the improvements in the early-course group in executive functioning were statistically significant and the improvements in working memory trended to significance. These findings suggested that older inpatients with schizophrenia maintain neuronal plasticity. Thus, CR should be considered as an adjunct treatment to usual PR services.This study had several limitations. The CR training sessions were designed to have a relatively low dose  due to the durations of inpatient hospitalizations. Even though the low CR dose was similar to those used in previous studies (van der Gaag et al., Despite the limitations noted above, the results of the current study highlight the importance of delivering CR within a PR context to middle-aged or older inpatients with chronic schizophrenia, especially to improve their executive functioning, which is a critical factor for learning in PR and treatment Green, .K-HC, S-HL, and T-YH designed the study. K-HC wrote the first draft of the manuscript and supervised cognitive remediation sessions, S-MK and JK administered cognitive remediation. S-MK, JK, and KP undertook the statistical analysis. S-CP supervised participants' recruitment and administration of psychotropic medications during trials. W-HL and SC supervised neurocognitive and clinical assessments. All the authors commented on the manuscript. All the authors contributed to and have approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Myocardial dysfunction occurs in a variety of fetal disorders. Findings from adult cardiology, where n-terminal pro-B-type natriuretic peptide (nt-proBNP) is an established biomarker of left ventricular dysfunction have been extended to fetal life. Since fetal blood sampling is technically challenging we investigated amniotic fluid nt-proBNP for its suitability to diagnose fetal myocardial dysfunction.Ultrasound, Doppler examination and echocardiography was applied to classify cases and controls. Amniotic fluid nt-proBNP to amniotic fluid total protein ratio was calculated and compared to the gestational age-dependent reference intervals. In a subset of cases, fetal and maternal plasma nt-proBNP levels were determined.Specimen from 391 fetuses could be analyzed . There was a high correlation between amniotic fluid and fetal blood nt-proBNP levels , whereas no correlation could be detected between maternal and fetal (blood and amniotic fluid) nt-proBNP concentrations. Specificity and positive likelihood ratio of amniotic fluid nt-proBNP to amniotic fluid total protein ratio were high .Amniotic fluid nt-proBNP measurement allows diagnostic confirmation of fetal myocardial dysfunction. It may serve as a useful adjunct in addition and correlation to existing tests of myocardial function, particularly in the context of invasive fetal therapy, where access to the amniotic cavity is part of the procedure. Myocardial dysfunction accompanies a variety of fetal conditions. These include not only structural cardiac defects, primary myocardial diseases and cardiomyopathies. Diseases which imply an increased cardiac output or altered intrathoracic volume relations , chronic twin-transfusion syndrome (TTS) in monochorionic pregnancies, and fetal growth restriction (FGR) have also been shown to impact on cardiac function –8. MinimIn adult and pediatric patients with heart failure, the cardiac peptide hormone B-type natriuretic peptide (BNP) or its inactive cleavage product, n-terminal pro-B-type natriuretic peptide (nt-proBNP) is an established biomarker for the diagnosis and management of myocardial dysfunction as it allows a comprehensive assessment of the myocardial structure, function and loading. Nt-proBNP- guided therapy has been incorporated into clinical practice –20. CardFetal blood sampling is a technically challenging procedure. In comparison, amniocentesis has a higher success and a lower complication rate. Additionally, access to the amniotic cavity is gained for invasive intrauterine therapies. Difficulties in quantitative amniotic fluid (AF) analysis however arise from the dynamic changes of its composition and volume. Urin and lung fluid are contributors of AF, swallowing and intramembranous transport reduce AF volume; the latter occurs at the amnion covering the placenta and allows direct exchange between AF and fetal blood. Hydrostatic and osmotic gradients additionally act on AF volume and composition. Despite these difficulties in AF reseach, available evidence allows the assumption that AF-nt-proBNP is of fetal origin –34.We previously established reference intervals for AF-nt-proBNP . The aimThe study was approved by the Medical School Ethics Committee of the University of Bonn (registration number 305/11). All participating women gave their written consent. Patients with gestational age (GA) between 10 and 34 weeks, presenting at our Center for Prenatal Diagnosis between November 2011 and March 2015 who were scheduled to undergo any invasive intervention that implies access to the amniotic cavity were eligible. No procedure was undertaken for the sole purpose of the study. Additionally, a subset of women who underwent scheduled cesarean delivery between 35 and 40 weeks of gestation were invited to participate. In all cases a detailed assessment of the fetal anatomy and cardiovascular status including echocardiography and Doppler examination was performed. We previously established reference values for AF-ntproBNP and extended these findings by further recruitment of controls. Classification of patients as cases and controls was undertaken according to the following criteria:Fetuses with conditions that imply an impact on the cardiovascular function such as cardiac, thoracic and urinary tract malformations, congenital diaphragmatic hernia, tumors or intrauterine infections with alterations in cardiovascular loading, chronic TTS, FGR and hydrops were classified as cases. Fetuses with cerebral and skeletal malformations, neural tube defects, and aneuploidies without associated malformations were assigned to the control group, which otherwise consisted of fetuses without any structural abnormality. Further classification criteria were estimated fetal weight, Doppler examination of the umbilical and middle cerebral artery, and qualitative echocardiography. Maternal exclusion criteria were the presence of cardiac or renal diseases. Inclusion and exclusion criteria for controls have been described in detail , 36.In a subset of patients, maternal and fetal blood samples were collected for analysis of hemoglobin and nt-proBNP concentrations. Neonatal notes were reviewed in all cases that ended in a life birth.A detailed description of the fetal assessment, including ultrasound technique, Doppler studies and echocardiography has been published . All exaNt-proBNP was analyzed with a commercially available chemiluminescence immunoassay on a Dimension Vista 1500, and amniotic fluid total protein concentration (AF-TP) by photometry on a Dimension RxL Max System . For nt-proBNP, inter- and intra-assay coefficients of variation were 3.5% and 2.3%, respectively. All samples were processed within two hours after retrieval.To adjust for a potential dilutional effect, the AF-nt-proBNP / AF-TP ratio was calculated and used for analysis. The previously established reference curve was extended to incorporate samples from 34 to 40 weeks of gestation , 37. NonIn total, 395 samples were collected. Fetal hemoglobin and plasma nt-proBNP concentrations were determined in 95 cases . A very good correlation was found between nt-proBNP concentration in amniotic fluid and fetal blood . Maternal plasma nt-proBNP concentrations, analyzed in a subset of women, were within normal range. No correlation was present between nt-proBNP levels in fetal and maternal blood .Specificity (0.97) and positive likelihood ratio (4.3) were high, whereas sensitivity and negative likelihood ratio were low .We examined nt-proBNP in amniotic fluid for its role as a biomarker of myocardial dysfunction in fetal medicine, analyzing a large group of fetuses with a broad variety of disorders. The low test sensitivity precludes its application for screening purposes. However, in case of suspected myocardial dysfunction, AF-nt-proBNP determination permits confirmation. It is the only investigation in fetal medicine not based on diagnostic imaging.Like other amniotic fluid constituents, AF-ntproBNP and AF-TP concentrations are affected by the multitude of compartments contributing to AF inflow and outflow, the hydrostatic and osmotic gradients, and the changes that occur during the course of pregnancy and in fetal disease. Although AF-ntproBNP is of fetal origin  we assumPrevious investigations on AF-ntproBNP were undertaken in chronic TTS. Here, concentrations correlated with the degree of myocardial dysfunction or disease severity. However, controls were either not available or of small sample size –41. A fuWe consider AF-nt-proBNP analysis a useful adjunct method in the assessment of fetuses with myocardial dysfunction, particularly in the rapidly expanding field of minimally invasive fetal therapy, since access to the amniotic cavity is part of the procedure. Criteria for case selection, intervention timing, prognosis establishment and treatment evaluation are still being established, and are based exclusively on diagnostic imaging. AF-nt-proBNP analysis and correlation with non-invasive methods of myocardial function assessment may provide further insight into the pathophysiology of fetal cardiac function and mechanisms of myocardial adaptation.Additionally, serial analyses of AF-nt-proBNP concentrations allow the assessment of myocardial changes after intrauterine procedures. In fetal anemia, serial analyses of circulating nt-proBNP levels revealed myocardial adaptations with potential long-term implications .Ideally, reference intervals should be constructed with datasets from healthy cases. Furthermore, a longitudinal rather than a cross-sectional study design should be applied. However, ethical considerations prohibit an intervention with inherent complications purely for research purposes. A general limitation of nt-proBNP analysis is the assay-specificity which makes comparisons of studies performed with different assays difficult , 44.Indications for prenatal invasive therapy are on the rise and diagnosis, intervention timing and treatment evaluation are limited to ultrasound-based methods. AF-nt-proBNP analysis may become an additional diagnostic tool in fetal medicine. Furthermore, serial analyses may permit insight into mechanisms of myocardial adaptation that occur as a result of altered loading conditions. Nevertheless, validiation with an independent dataset is required.S1 Table(SAV)Click here for additional data file.


Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis. Because of their anti-inflammatory and anti-fibrotic effects, angiotensin receptor blockers (ARBs) are potential therapeutic agents for NAFLD. The present systematic review assessed the effectiveness of ARBs in NAFLD management.P = 0.10), a fixed-effect model revealed a decreasing trend in alanine transaminase levels. Low-density lipoprotein levels were reduced by ARB treatment , and total cholesterol also decreased in response to ARBs . However, the fibrosis score and NAFLD activity score were not significantly improved by ARB treatment  .Accounting for data overlap and exclusion criteria, randomized controlled trial -based and single-arm meta-analyses were conducted for four studies with 362 patients and eight studies with 525 patients, respectively. Although alanine aminotransferase levels were not significantly affected by ARB treatment  ; Keywords were used to identify studies in PubMed, EMBASE, CENTRAL, Web of Science and CNKI published up to July 31, 2017. Single-arm and RCT-based meta-analyses of the available data were performed using RevMan (version 5.3).Although ARBs significantly decreased plasma low-density lipoprotein and total cholesterol levels, the current evidence is insufficient to support the efficacy of ARBs in managing fibrosis in NAFLD patients. Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis . The majRecently, the renin-angiotensin-aldosterone system (RAAS), which has a central function in the physiology of blood pressure, was reported to be associated with inflammation and fibrosis in NAFLD . MoreoveARBs have also been found to regulate hepatic lipid metabolism . Lipid aAlthough the functions of ACEIs and ARBs in preventing complications of NAFLD have been widely investigated in mice, clinical data from patients are lacking,  and the An extensive electronic search was performed by two independent investigators (YT and XH) for relevant articles published up to July 31, 2017. Databases including PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and China National Knowledge Infrastructure (CNKI) were searched. The searches were performed using medical subject headings (MeSH) combined with the following terms: ‘non-alcoholic fatty liver disease’, ‘angiotensin receptor blockers’, ‘renin-angiotensin-aldosterone system’, and the names of specific ARBs, including valsartan, telmisartan, losartan, irbesartan, azilsartan and olmesartan. The references of relevant review articles were manually searched to identify applicable studies. The publication language was not restricted. Relevant RCTs were manually selected.Two investigators (YT and XH) independently assessed the eligibility of the identified articles. Titles and abstracts were first screened, and eligible articles were reserved for full-text review. No language restriction was imposed for inclusion. Studies meeting the following inclusion criteria were included: (1) articles including patients with NAFLD, (2) studies on patients treated with ARBs, and (3) studies reporting data on the therapeutic effects of ARBs. The exclusion criteria were as follows: (1) case reports, editorials or review articles; (2) studies involving treatment of NAFLD with strategies other than ARBs; and (3) studies in which the patients’ condition was complicated, such that the therapeutic effect may have been affected by other treatments without any control variate method. Any disagreement or doubts were resolved through discussion to reach a consensus.The following data were extracted by the two investigators: year of publication, number of patients, characteristics of patients , location and period of the study, detailed dosage and categories of ARB used for NAFLD, clinical outcomes including F-S, NAS, and HOMA-IR, alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC) levels, and body mass index (BMI). Data extraction was performed by reading the full articles, tables, figures and interpretations for each included study. Any disagreements were resolved by reaching a consensus.The risk of bias was assessed with the Cochrane Collaboration’s risk of bias tool based on seven domains: random sequence generation, allocation concealment, blinding of participants and outcome assessment, incomplete data, selective reporting, intention to treat analysis, and other sources of bias. Disagreements were resolved by consensus.All selected articles involving RCTs were assessed for the risk of bias according to Cochrane Handbook for Systematic Reviews of Interventions, which mainly includes seven domains: (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome assessment (detection bias), (5) incomplete outcome data (attrition bias), (6) selective reporting (reporting bias), and (7) other bias. The risk of bias in each category was designated as low or high; it was designated as “NA” if the risk was not applicable to the particular study.2 statistic, with α = 0.05. The fixed-effect model was used if there was no evidence of heterogeneity when I2 ≤ 50%; otherwise the random-effect model was employed. Subgroup analysis was performed by grouping similar types of ARBs to reduce significant heterogeneity.RevMan software (version 5.3) was used to pool all appropriate data including NAS and HOMA-IR indices, ALT, AST, GGT, LDL, HDL, TC levels and BMI. Single-arm and RCT-based meta-analyses were performed for each parameter if the data were available. The mean difference (MD) and 95% confidence interval (CI) were calculated. The standardized mean difference (SMD) was employed when different instruments were used to measure the same construct. Heterogeneity of the included studies was assessed and quantified using the IAccording to the selection process shown in Figure Among the eight included clinical trials, five included patients diagnosed with NASH based on histology; the other three enrolled NAFLD patients. In four studies, losartan was administered at a dose of 50 mg/d or 100 mg/d for at least four months. Telmisartan, valsartan and olmesartan were also used in other studies, with treatment durations ranging from two to 12 months. The study by Alam et al.  recommenThe quality of the included studies was moderate to high according to the Cochrane Collaboration’s risk of bias tool. The summary of quality assessment domains of the included studies is shown in Figure P < 0.00001; I2 = 95%), indicating that serum ALT levels were significantly reduced during ARB treatment of NAFLD . The random-effect model was used because of significant heterogeneity . Although the results were not significant , and AST levels were found to be significantly reduced in response to ARB treatment , and the results were similar to those obtained for ALT ; P = 0.29; Figure Five trials reported controversial results regarding AST levels in the ARB-treated group. A single-arm meta-analysis was performed with the random-effect model , the random-effect model was adopted, which showed that GGT levels were significantly reduced in response to ARBs . Because significant heterogeneity was observed across the studies , the random-effect model was employed. The results indicated that ARB did indeed reduce HOMA-IR . Because significant heterogeneity was observed . Despite the lack of statistical significance, ARB did decrease LDL levels . Therefore, ARB treatment reduced LDL levels  and RCT-based  meta-analyses. However, no improvement in HDL levels was observed in response to ARBs in either meta-analysis , but the fixed-effect model was used in the RCT-based meta-analysis . ARB appeared to reduce TC levels in both meta-analyses, albeit in a non-significant manner  showed a significant reduction in F-S in response to ARB treatment  failed to reveal any significant difference in response to ARB treatment , and the results showed the NAS to be significantly reduced by ARB treatment  failed to show a significant improvement in the NAS by ARBs compared with the control treatment  and RCT-based  meta-analyses. The former analysis indicated that BMI was significantly reduced following treatment with ARBs  is known to promote various cellular and molecular pathophysiological processes. Here, we attempt to assess the effects of ARBs on patients with NAFLD or NASH and to study whether ARBs can decrease hepatic histology scores and plasma liver enzyme activities as well as ameliorate histological changes.This systematic review includes results from RCT-based meta-analyses of four studies including 362 patients and single-arm meta-analysis of eight studies including 525 patients. To the best of our knowledge, this is the first RCT-based meta-analysis conducted to comprehensively evaluate the therapeutic effects of ARBs on patients with NAFLD. Our results support the use of ARBs as a practical and effective treatment strategy for patients with NAFLD, particularly because of the reductions in TC and LDL levels.A small fraction of the RCTs included in this review reported significant differences between the ARB and placebo groups in terms of ALT levels. However, our pooled analysis demonstrated a clear downward trend in ALT levels, even though this decrease did not reach statistical significance. Consistent with our results from single-arm meta-analysis, a cross-sectional study of 290 hypertensive patients with NAFLD reported that AST levels were significantly lower in patients receiving ARBs than those in patients not treated with ARBs .Telmisartan and valsartan are both commonly used in the clinic, and these drugs have been reported to improve ALT levels . Forty-eIR is observed in approximately 95% of NAFLD patients  and is rn = 197), though HDL levels were not significantly altered. In the study by Derosa et al., patients with T2DM (n = 116) were treated with telmisartan (40 mg/day) [P < 0.01 vs baseline) and LDL  levels were observed. In contrast to valsartan, which lacks lipid-lowering effects, the PPAR-gamma ligand effect of telmisartan enables it to ameliorate IR, and this likely contributes to its beneficial effects on the lipid profile [Our RCT-based meta-analysis revealed lipid profile amelioration by ARBs, as indicated by the lower levels of plasma LDL and TC, consistent with previous findings –38. Telm mg/day)  for 12 mmisartan  mg/day [Nevertheless, a study by Ichikawa et al. showed that telmisartan treatment did not affect, TC, HDL or LDL levels , 41, 42.Based on our single-arm meta-analyses, we cautiously speculate that ARB treatment plus lifestyle modification may have a greater impact on lowering LDL levels than ARB treatment alone.®-CAP), than patients without ARB treatment [Our pooled analysis showed a lack of beneficial effect of ARBs on fibrosis and NAS, which is consistent with the findings of McPherson et al.,  despite reatment . Howeverreatment . Moreovereatment , 43, 44.reatment , 21, 23.reatment . HoweverThe main reason for the controversial results in the current meta-analysis may because of the small number of included studies. Histopathological examination is the gold standard for the diagnosis of NASH, but it is limited due to its invasive nature. Non-invasive tests such as ultrasonography and fibroscanning were performed for some of the included patients, which accounted for the fewer number of patients undergoing liver biopsy. Assessment of the degree of heterogeneity may not be reliable in such a small number of studies, and this may contribute to the lack of certainty in the results. Moreover, 7.1 years  are typihttp://handbook-5-1.cochrane.org/). Therefore, the results need to be treated with caution; analysis of existing clinical data may enable us to identify additional studies.There are certain limitations of our study. Because only a handful of commonly established non-invasive biomarkers have been used in clinical trials of NAFLD/NASH, primary outcomes were assessed based on histological and biochemical markers such as liver enzymes, liver histology, degree of fibrosis and lack of invasion via TE. Results that are beyond the shared characteristics of the included study population cannot be generalized. Moreover, methodological differences and variable durations of treatment can lead to significant statistical heterogeneity, which cannot be solved by subgroup analysis. As negative results are less likely to be published, our search was confined in that regard as well. Due to the limited number of existing studies, it was difficult to perform publication bias analysis. The Cochrane handbook indicates that tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta-analysis, as the power of the test is too low to distinguish chance from real asymmetry when studies are involved (We draw the following conclusion cautiously: although ARBs can significantly decrease plasma LDL and TC levels, current evidence is insufficient to support the efficacy of ARB in the management of fibrosis and HOMA-IR in NAFLD patients. Further clinical trials with larger sample sizes and longer follow-up durations are needed to strengthen the evidence for the efficacy of ARBs in treating NAFLD.As all reviews and analyses were based on previously published studies, no ethical approval was necessary.


Vitiligo is a common pigment disorder characterized by acquired loss of function or absence of melanocytes, leading to distinct areas of depigmentation. Physical exam reveals sharply demarcated, depigmented macules or patches on otherwise normal skin. Vitiligo can present at any age, in any skin color. There is no specific serologic marker for diagnosis, but patients often have other autoimmune problems. Treatment options are limited and are difficult given the fact that the pathogenesis of the disease is not well elucidated. We present the case of a 52-year-old woman with vitiligo for over 2 decades. The patient's medical history reveals a lack of response to many different approaches. This case highlights the ability of apremilast, an FDA-approved drug for the treatment of psoriasis and psoriatic arthritis, to achieve repigmentation in a case a vitiligo that has been extremely recalcitrant. Vitiligo is a common pigment disorder characterized by acquired development of white macules on the skin due to the loss of functioning melanocytes in the skin, the hair, or both . AlthougAlthough topical and systemic glucocorticoids, topical calcineurin inhibitors, and narrowband ultraviolet B phototherapy are used to promote repigmentation, they all have varying degrees of success , 5, 6. TA 52-year-old woman presented for a follow-up of chronic vitiligo. No other concomitant autoimmune diseases are known in this patient. She developed vitiligo in 1995 and has been seen in this clinic since 1998. She used topical tacrolimus, pimecrolimus, mometasone furoate cream, clobetasol propionate cream, topical psoralen combined with photochemotherapy with UVA, intramuscular triamcinolone acetonide, intramuscular alefacept, subcutaneous etanercept, oral cyclosporine, oral dapsone, and oral prednisone in the past. The patient stopped the use of medications for 5 years prior to re-presenting due to lack of success with repigmentation with the previously listed medications. Her attempt at multiple non-FDA-approved medications illustrates her frustration. At the first visit, the diagnosis of chronic vitiligo was readdressed. The recent data suggesting that apremilast may have a broad effect on inflammation was reviewed and the patient was willing to try apremilast in a non-FDA-approved fashion . After sThe treatment of vitiligo is challenging given the lack of well controlled studies and inability to pool results based on considerable heterogeneity in study design and outcome measure. Apremilast has been shown to help in autoimmunity from alopecia areata . Our casα, and interleukin- (IL-) 17, IL-23, and interferon gamma, as well as increased IL-10) [ vitiligo, apremilast, and re-pigmentation revealed that there currently are no known cases of repigmentation in patients with vitiligo on apremilast that have been reported. Our patient presented with chronic vitiligo that was extremely recalcitrant to many different classes of drugs and modalities of delivery.Apremilast is a phosphodiesterase-4 enzyme (PDE-4) inhibitor. Apremilast is FDA-approved for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, as well as for use in psoriatic arthritis. PDE-4 normally degrades cyclic adenosine monophosphate (cAMP) into 5′-adenosine monophosphate. By inhibiting the PDE-4 enzyme specific for cAMP degradation, this results in increased intracellular cAMP levels and thereby regulation of numerous inflammatory mediators through the cAMP second messenger effect  . When ind IL-10) –10. Melad IL-10) . Positivd IL-10) . IL-6 and IL-10) . Recent d IL-10) . The used IL-10) . There aPsoriasis, alopecia areata, and vitiligo share a common pathway of autoimmunity, inflammatory signals, and cytokines present, although their pathogenesis is not completely understood. Apremilast is FDA-approved for psoriasis and psoriatic arthritis. Apremilast has also been shown to inhibit the development of alopecia areata . We presTimeline showing the patient's continual use of apremilast 30 mg BID and when steroid bolstering occured.


As part of research on the heart–brain axis, we investigated the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with brain structure and function in a community-based cohort of middle-aged adults from the Brain Magnetic Resonance Imaging sub-study of the Coronary Artery Risk Development in Young Adults (CARDIA) Study.p = 0.003), even after additionally adjusting for cardiac output . Higher NT-proBNP levels were also associated with lower DSST scores. NT-proBNP was not related to WM volume, WM integrity, or abnormal WM load.In a cohort of 634 community-dwelling adults with a mean (range) age of 50.4 (46–52) years, we examined the cross-sectional association of NT-proBNP to total, gray (GM) and white matter (WM) volumes, abnormal WM load and WM integrity, and to cognitive function tests . These associations were examined using linear regression models adjusted for demographic and cardiovascular risk factors and cardiac output. Higher NT-proBNP concentration was significantly associated with smaller GM volume (β = −3.44; 95% CI = −5.32, −0.53; In this middle-aged cohort, subclinical levels of NT-proBNP were related to brain function and specifically to GM and not WM measures, extending similar findings in older cohorts. Further research is warranted into biomarkers of cardiac dysfunction as a target for early markers of a brain at risk. Several studies suggest a role for cardiac health in processes relating to brain atrophy and cognitive impairment at older age, leading to hypotheses concerning the heart–brain axis –4. TheseOne promising biomarker of this axis is amino-terminal pro-brain natriuretic peptide (NT-proBNP), which is released from proBNP along with the physiological active BNP, in response to ventricular wall shear stress. BNP regulates systemic fluid volume through vasodilatation and natriuresis, in part by antagonizing the renin–angiotensin–aldosterone axis . NT-proBThe direct physiological function and clinical relevance of peripheral BNP release on the central nervous system is not fully understood. However, the presence in the brain of widely distributed receptors of the natriuretic peptides, including B-type, suggests additional pathways between the heart and brain, which may contribute to later age cognitive impairment . ConsistHere, we investigated the association of NT-proBNP to several magnetic resonance imaging (MRI) measures that have been linked to neurocognitive pathology, including total brain volume, gray matter (GM) volume, white matter (WM) volume, abnormal WM load, and WM microstructural integrity  in a well characterized bi-racial, middle-aged community-based sample participating in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort.We hypothesized that higher NT-proBNP is associated with an MRI profile reflective of relatively higher load of macro and microstructural alterations. In secondary analyses, we further investigated the association of NT-proBNP to cognitive function and to GM lobar tissue volumes.n = 5,115) occurred at sites in four US cities . Participants were then followed for 25 years through seven follow-up study visits (response rate at the Y25 exam was 72%).This study is based on a cross-sectional analysis of data collected in a subsample of the 25th year follow-up exam participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a longitudinal study started in 1985 to investigate cardiovascular risk factors in a bi-racial (white/black) cohort of community-dwelling adults aged 18–30 years at baseline. Recruitment of the cohort (n = 252) from Oakland, 41.3% (n = 297) from Minnesota, and 23.6% (n = 170) from Birmingham.At the 25th year of follow-up, participants from three of the four CARDIA study centers  were invited to take part in the CARDIA Brain MRI study. This sub-study aimed to identify structural and functional brain changes associated with cardiovascular risk factor trajectories . ExcludiThe CARDIA Brain sub-study was carried out in accordance with the recommendations of site-participating local institutional review boards (IRBs) with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the IRB covering intramural research at the National Institute on Aging.N-terminal pro-brain natriuretic peptide concentration was measured from Year 25 samples using the proBNP II electrochemiluminescence immunoassay on a Cobas e411 chemistry analyzer . The measuring range is 5–35,000 pg/mL (defined by the lower detection limit and the maximum of the standard curve). The inter-assay coefficient of variation is less than 5%. All NT-proBNP assays were performed in the Laboratory for Biochemistry Research at the University of Vermont.As previously described , brain sThe preprocessing of the T1-weighted scan involved brain extraction  using a multi-atlas segmentation method , correctThe brain volumes of interest in this study were total brain volume, total GM volume, and total WM volume, as well as lobar GM volumes in the frontal, temporal, and parietal lobes. Regional GM volumes include abnormal and normal tissue; abnormal tissue volume was very low in our cohort. We also investigated the association of NT-proBNP to abnormal WM volume which includes WM tissue damage due to ischemia, demyelination, inflammation, and damaged penumbra tissue surrounding focal infarcts. Because abnormal WM load was low in our sample, we categorized it into high  versus no-to-low abnormal WM. We evaluated WM integrity, measured using fractional anisotropy from diffusion tensor imaging with higher values indicating better signal diffusion along WM tracts , 22.z-scores prior to analysis.Three cognitive function tests were performed as part of the core CARDIA Year 25 exam. All cognitive tests were conducted and scored by a certified technician. A script was used for each test and the tests were performed in the same order across subjects to enhance standardization. The Digit Symbol Substitution Test (DSST) assesses cognitive speed, attention, and concentration , 24. The2), systolic and diastolic blood pressure measurements (average of the second and third blood pressure readings), total cholesterol (mg/dL), glomerular filtration rate (GFR) [estimated using a standard equation that includes serum creatinine concentration, sex, age, and race (n = 14) were replaced with values acquired from a previous exam.In our analysis, we accounted for the following potential confounding variables, measured at the Year 25 exam, which were associated with either NT-proBNP and brain volumes in our sample or in prior literature: age, sex, race, total intracranial volume (to correct for head size), education , smoking status , body mass index  .Of the 719 subjects participating in the Year 25 MRI exam, 654 had plasma samples drawn at the same exam the MRI was acquired. Of those, 634 subjects had successfully assayed NT-proBNP levels and successfully processed structural MRI scans and these constituted our analytical sample for the brain volume analyses. Among these individuals, five had clinical levels of >400 pg/mL. Cardiac output was measured in a subset of 564 participants. Fractional anisotropy was measured in subset of 626 participants, and of those, 556 had cardiac output data.Descriptive measures are reported for the whole sample and across tertiles of NT-proBNP. Differences in covariates across NT-proBNP tertiles were tested with chi-square for categorical variables and analysis of variance for continuous variables. We used ordinary least squares linear regression models to estimate the associations of NT-proBNP to total brain, total GM, and WM volumes, as well as regional brain volumes, WM integrity, and cognition. Logistic regression models were used for abnormal WM load to compare the top 15% of the sample with the rest of the cohort.The distribution of NT-proBNP levels was right-skewed  that corresponded to the mean NT-proBNP for each decile of NT-proBNP. As our sample and others  showed tAll analyses were performed using R Statistical Software , versionThe mean age in our sample was 50.4 years with a range of 46–52 years: 52% were female, 61.5% were Caucasian, and 38.5% were African-American , but not with total WM volume  after adjusting for potential confounders in both Model 1 and the fully adjusted Model 2 . Results of Models 1 and 2 were attenuated but remained significant at p < 0.02 when they were rerun on the subsample of 564 with cardiac output data .In sensitivity analyses, removal of the five subjects with NT-proBNP concentrations greater than 400 pg/mL  did not substantially change the association between NT-proBNP and total GM . We additionally explored whether the association was modified by race, body mass index, and renal function, given their potentially important relationships to NT-proBNP (p for interaction terms > 0.27).The association of NT-proBNP and total GM volume was not significantly different between men and women , which were attenuated when cardiac output was taken into account (p > 0.1 in Model 3).Higher NT-proBNP levels were associated with smaller temporal GM volume in the fully adjusted model .Association with cognitive function: Higher NT-proBNP levels were associated with significantly lower DSST scores  contributed to the observed association between NT-proBNP and GM volume, even though we adjusted for a number of cardiovascular risk factors. Another issue concerns the fully automated procedures of brain volume estimation, which are optimal for large community-based studies, but can potentially include measurements error due to residual inter-subject variability. However, the errors are unlikely to be systematically related to NT-proBNP and to be driving our results.We observed a significant association between higher NT-proBNP concentration and lower total GM volume, but not total WM volume or WM integrity and abnormalities, in a bi-racial cohort of 634 community-dwelling participants with a mean age of 50 years. This association was significant after adjusting for cardiovascular risk factors as well as cardiac output. Higher NT-proBNP concentrations were also associated with poorer processing speed. Our findings highlight a potentially differential relationship between subclinical markers of cardiac health and GM tissue at younger age and motivate further research into biomarkers of cardiac dysfunction as early markers of a brain at risk and into the temporal succession of the deterioration of brain health in relation to cardiac pathology.The CARDIA brain sub-study was carried out in accordance with the recommendations of site-participating local IRBs with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the IRB covering intramural research at the National Institute on Aging.IF: analysis and interpretation of data and drafting and revising the manuscript. ME: analysis and interpretation of data and revising the manuscript. BS, RT, and NB: interpretation of data and critical review of the manuscript. DJ and OM: analysis, critical review of the manuscript, and interpretation of data. OS: critical review of the manuscript. LL: conception and study design, analysis and interpretation of data, and revising the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewers KR and handling Editor declared their shared affiliation.


The amygdala and the dorsolateral prefrontal cortex (DLPFC) play important roles in “emotion dysregulation,” which has a profound impact on etiologic research of generalized anxiety disorder (GAD). The present study analyzed both eyes-open and eyes-closed resting state functional MRI (rs-fMRI) of 43 subjects . The amygdala and the DLPFC were defined as regions of interest (ROI) to analyze functional connectivity (FC) in GAD patients compared with healthy controls. The main findings revealed GAD patients had increased FC between the amygdala and the temporal pole compared to healthy controls, which was found in both eyes-open and eyes-closed rs-fMRI. And altered FC between the ROIs and brain regions that mainly belonged to the default mode network (DMN) were found. These findings suggest that the abnormal FC between the amygdala and the temporal pole may contribute to the pathophysiology of GAD, and provide insights into the current understanding of the emotion dysregulation of anxiety disorders. Anxiety disorders are the most common of all mental disorders with 30% prevalence in the population, and they significantly contribute to the economic burden of disease , an important region for performing cognitive operations during the regulation of emotional responses, has been shown to play a key role in the pathophysiology of GAD  to explore in GAD patients. Because the number of volumes in the eyes-open resting state fMRI (rs-fMRI) we collected was too small, we also analyzed the eyes-closed rs-fMRI using the same protocol to improve the reliability of our results.All participants received the Mini-International Neuropsychiatric Interview (MINI), Chinese version . Written informed consent was acquired from every participant.All participants were informed of the safety and eligibility criteria for fMRI scanning: no neurological conditions and no implanted ferrous metal. The Hamilton Rating Scale for Anxiety (HAMA)  with a standard 12-channel head coil. Restraining foam pads was used to reduce head motion and earplugs were used to reduce scanner noise. High-resolution T1-weighted anatomical images (repetition time (TR) = 1900 ms, echo time (TE) = 2.46 ms, flip angle = 9 degrees, 32 transverse slices, field of view (FOV) = 240 × 240 mm, matrix = 256 × 256, slice thickness = 1 mm) were acquired using a magnetization prepared rapid gradient-echo sequence. Resting-state functional MRI data were acquired using a single-shot, gradient-recalled echo planar imaging sequence . 32 transverse slices  resulting in a total of 80/157 volumes and a scan time of 164/314 s, respectively, in eyes-open and eyes-closed rs-fMRI. During the scan, participants were instructed to stay aware. After the scan, the technicians would check the quality of structural images. If any abnormalities were found in the images, participants were re-scanned.t-tests for continuous variables and chi-square tests for categorical variables were used.Using Statistical Product and Service Solutions software 17.0 , we conducted analysis of age, gender, years of education, HAMA, and HAMD. Independent sample http://restfmri.net/forum/)  . Both t-tests and correlation analysis were conducted under the BrainMask_61*73*61. As correction for multiple comparisons, a corrected threshold of p < 0.05 (two-tailed) was derived from a combined threshold of p < 0.005 for individual voxel with a cluster size >53 voxels. These threshold were determined using the 3dFWHM and 3dClustSim program in AFNI software . Additionally, age, years of education, HAMD score and intracranial volume (ICV) were modeled as covariates. The analyses above were conducted in both eyes-open and eyes-closed rs-fMRI.According to previous studies . Except that, there is no significant difference between GAD patients and healthy controls.Compared with the healthy control group, the HAMA scores and HAMD scores were significantly different in GAD patients .Compared with healthy controls, GAD patients showed increased FC between the left amygdala and the temporal pole both in eyes-open and eyes-closed rs-fMRI . . Decreased FC between the left DLPFC and the precuneus, the lingual gyrus, the calcarine sulcus, and the cerebellar vermis was detected in GAD subjects compared with healthy controls . There was decreased connectivity between the right DLPFC and the medial prefrontal cortex (mPFC), the dorsal anterior cingulate cortex (dACC), the middle temporal gyrus, the angular gyrus, the precuneus, the calcarine sulcus, and the cerebellar vermis in GAD subjects compared with healthy controls . . The FC between the right amygdala and the fusiform gyrus, the superior/middle occipital gyrus, and the cerebellum was positively correlated to the HAMA score in GAD subjects . We found that the HAMA score was positively correlated with the FC between the DLPFC and the inferior frontal gyrus, the supplementary motor area (SMA), and the cerebellum in GAD subjects . . , 0.271 (eyes-closed)].Additionally, both in eyes-open and eyes-closed rs-fMRI, we did not find a significant difference in frame-wise displacement between GAD patients and healthy controls [In this study, we conducted analysis to characterize alterations in FC that may show the pathological basis of GAD using both the eyes-open and the eyes-closed rs-fMRI. While exploring FC seeded from the amygdala and the DLPFC, we found: (1) Patients with GAD showed increased FC between the left amygdala and the temporal pole compared with health controls. (2) In both eyes-open and eyes-closed conditions, the brain regions showed altered FC with amygdala/DLPFC were primarily from the default mode network (DMN).Increased FC between the amygdala and the temporal pole was detected by both eyes-open and eyes-closed rs-fMRI. This finding may illustrate that the altered FC may contribute to the etiology of GAD. Previous findings indicate that the temporal pole plays a role in both social and emotional processing, including specific recognition, theory of mind  is defined as the set of regions in the brain that are consistently more activated during resting condition than other brain networks . Functional abnormalities of these regions reflect excessive vigilance as a hallmark of anxiety disorders. The VN is associated with pathological memories and planning a response to potentially threatening stimuli  and repetitive transcranial magnetic stimulation (rTMS) in curing GAD, the outcomes are various. According to our findings, we prefer the temporal pole as the stimulated target. By decreasing the related abnormal FC may remit anxiety in GAD patients.In conclusion, our study found altered FC seeded from the amygdala and the DLPFC in GAD patients using eyes-open and eyes-closed rs-fMRI. We found that the increased FC between the amygdala and the temporal pole may be underlying the neural pathophysiology of GAD. We hope these findings will shed light on the current understanding of GAD and on advanced therapeutic interventions.A limitation in this study is that we were only able to acquire 164 s in the eyes-open resting state fMRI data and the reliability of FC analysis under this condition is limited (to CL and ZY), Shanghai Health System Leadership in Health Research Program (XBR2011005) (to CL), Shanghai Health Bureau Project (2013SY003) (to JW), the Science and Technology Commission of Shanghai Municipality  , Shanghai Clinical Center for Mental Disorders (2014), National Key Clinical Disciplines at Shanghai Mental Health Center (to HC), Beijing Nova Program for Science and Technology (XXJH2015B079)(to ZY), Pfizer Investigator Initiation Research Fund (WI173560)(to CL) and Chinese Government Scholarship (CSC NO.201606230115)(to WL).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.


ATS-mainly  and ketamine-only (n=38) vs. ketamine-mainly . We used the Chinese Brief Psychiatric Rating Scale (BPRS) to assess these patients’ psychotic symptoms. ATS-mainly group had more anxiety/depression and anergia symptoms than ATS-only group (p<0.001), and ketamine-mainly group had more thinking-disorder, activity and hostility-suspicion symptoms than ketamine-only group (p≤0.001). These findings indicate that ATS may exacerbate the thinking-disorders, activity and hostility-suspicion symptoms of ketamine users, and ketamine may exacerbate anxiety/depression and anergia symptoms of ATS users.The use of amphetamine-type stimulants (ATS) and ketamine is of particular clinical concern because of its associated psychotic symptoms. In Chinese clinical practice, ATS and ketamine are commonly used simultaneously, but very few studies have reported the symptom profile of users who use both drugs. This study determined whether the combined use of ATS and ketamine is associated with more psychotic symptoms than either ATS or ketamine alone. According to drug use characteristics, 375 Chinese synthetic drug users were categorized into 2 pairs of comparison groups: ATS-only ( Over the past 2 decades, amphetamine-type stimulants (ATS) and ketamine have become increasingly prevalent in China -3. AccorPrevious research indicates that chronic/heavy ATS or ketamine use may induce psychotic symptoms resembling positive symptoms of schizophrenia, such as suspiciousness, delusions of persecution and hallucinations , 13, perThe current study examined psychotic symptoms among adult inpatients who diagnosed with ATS and/or Ketamine induced psychosis. To determine the synthetic effects of combined ATS and ketamine use on users’ psychiatric symptom profiles, we compared psychotic symptoms between patients who use both ATS and ketamine, and ATS or ketamine alone.The majority of participants in our sample were young males with low education levels and unstable jobs. Detailed demographic and drug use characteristics for the 4 groups were shown in Table p < 0.001), and ketamine-mainly group had more thinking-disorder, activity and hostility-suspicion symptoms than ketamine-only group (P ≤ 0.001). Overall, while there was no significant difference in BPRS total score between ATS-mainly and ATS-only groups (P = 0.217), ketamine-mainly group scored significantly higher on BPRS than ketamine-only group (P ≤ 0.001).As displayed in Table In this study, we found that the anxiety/depression and anergia symptom scores of ATS-mainly group were significantly higher than ATS-only group, while the total BPRS score, thought disorder, activity score and hostility-suspicion symptoms of ketamine-mainly group were more prevalent than ketamine-only group. These results suggest that the psychotic symptoms induced by the combined use of ATS and ketamine are more severe than those induced by ATS/ ketamine alone. Our data indicate that ketamine use may exacerbate depression and anergia symptoms of ATS users and, ATS may exacerbate the thinking-disorders, activity and hostility-suspicion symptoms of ketamine users.Consistent with 2 earlier studies , 22, ourThere are some methodological limitations in this study. Firstly, this was an observational study, and we were not able to control all possible confounding factors such as the dosage of drugs that influence psychotic symptoms. Secondly, our study participants were inpatients from a large psychiatric specialty hospital. Some of them were admitted involuntarily and therefore these drug users may tend to be more aggressive and offensive. Hence, findings from this study may not be generalizable to other clinical settings. Thirdly, another commonly used scale of psychotic symptoms, the Positive and Negative Syndrome Scale (PANSS), which is more comprehensive in assessing psychotic symptoms than BPRS , was notIn summary, this study provides some evidence of psychotic symptomatology for the synergistic effect of dual use of ATS and ketamine. It might be due to the interactions of NMDA glutamate receptor and monoaminergic systems in the human brain. One of the potential clinical implications is that ATS and ketamine may have different effects on psychopathology. Further mechanism research is needed to clarify the interaction between amphetamine and ketamine.Between January 2012 and December 2013, a total of 375 synthetic drug users admitted to the Drug Abuse Treatment Inpatient Ward of Wuhan Mental Health Center, were consecutively included in this study. The inclusion criteria were (1) met the criteria for “mental disorders due to psychoactive substance use/abuse” based on ICD-10 , 36, andn = 125) vs. ATS-mainly group , and ketamine-only group  vs. ketamine-mainly group (used ATS most of the time and ketamine sometimes) (n = 62). This study protocol was approved by the Ethics Committee of Wuhan Mental Health Center. All participants gave written informed consent.According to patients’ self-reported drug use patterns, we divided all patients into 2 pairs of comparison groups: ATS-only group (used ATS only)  and urine samples for urine toxicology tests. Enzyme multiplied immunoassay technique was used in urine tests to determine the types of drugs used, including ATS, ketamine, heroin, methadone, cocaine, cannabis, and benzodiazepines. Drug use history was reported by patients, and additionally verified by urine drug test results and their family members.On the day of admission, the Chinese Brief Psychiatric Rating Scale (BPRS) , 38 was t-test was used to compare the symptom scores between patients used dual drugs and a single drug. Chi-square test was used to compare the group differences for category variables. The statistical significance level was set at p < 0.05 (two-sided).All statistical procedures were carried out by using SPSS 20.0 for Windows. Independent sample