Exploring the impacts of age at menarche on cognitive aging in late adulthood: Evidence from a Mendelian randomization study on the Taiwanese population.

INTRODUCTION: The potential influence of age at menarche (AM) on cognitive aging remains inadequate, partly because of the difficulties presented by multiple confounders. To address this issue, the Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on cognitive aging. METHODS: Using the publicly accessible Taiwan Biobank, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM as instrumental variables to estimate the effects of instruments on cognitive function assessed with the Mini-Mental State Examination (MMSE). We employed several MR methods, including two-stage least squares, inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and constrained maximum-likelihood (cML) MR methods, to ensure the stability and reliability of the results. RESULTS: MR analyses indicated no significant causal relationship between genetically determined AMs and total and subdomain MMSE scores, except the G5 subdomain (ßIVW = 0.156, 95% confidence interval [CI]: 0.005, 0.307; ßcML = 0.161, 95% CI: 0.014, 0.309). However, in a leave-one-out sensitivity analysis, we found a significant relationship between AM and cognitive aging after eliminating rs157863 and rs6758290, thus demonstrating the potential pleiotropic effects of these two SNPs. After these two SNPs were eliminated, a significant causal relationship between AM and overall MMSE scores (ßIVW = 0.425, 95% CI 0.011, 0.839), though. CONCLUSION: Evidence from the present MR study did not fully support a causal relationship between AM and cognitive function decline in later life. Potential pleiotropic effects of the genes underlying these two traits are worth of further investigation.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Shared Genetics between Age at Menarche and Type 2 Diabetes Mellitus: Genome-Wide Genetic Correlation Study.

Background: Age at menarche (AAM) has been associated with type 2 diabetes mellitus (T2DM). However, little is known about their shared heritability. Methods: Our data comes from the Taiwan Biobank. Genome-wide association studies (GWASs) were conducted to identify single-nucleotide polymorphisms (SNPs) related to AAM-, T2DM-, and T2DM-related phenotypes, such as body fat percentage (BFP), fasting blood glucose (FBG), and hemoglobin A1C (HbA1C). Further, the conditional false discovery rate (cFDR) method was applied to examine the shared genetic signals. Results: Conditioning on AAM, Quantile-quantile plots showed an earlier departure from the diagonal line among SNPs associated with BFP and FBG, indicating pleiotropic enrichments among AAM and these traits. Further, the cFDR analysis found 39 independent pleiotropic loci that may underlie the AAM-T2DM association. Among them, FN3KRP rs1046896 (cFDR = 6.84 × 10-49), CDKAL1 rs2206734 (cFDR = 6.48 × 10-10), B3GNTL1 rs58431774 (cFDR = 2.95 × 10-10), G6PC2 rs1402837 (cFDR = 1.82 × 10-8), and KCNQ1 rs60808706 (cFDR = 9.49 × 10-8) were highlighted for their significant genetic enrichment. The protein-protein interaction analysis revealed a significantly enriched network among novel discovered genes that were mostly found to be involved in the insulin and glucagon signaling pathways. Conclusions: Our study highlights potential pleiotropic effects across AAM and T2DM. This may shed light on identifying the genetic causes of T2DM.

High-Fat Diet Exacerbates Autistic-Like Restricted Repetitive Behaviors and Social Abnormalities in CC2D1A Conditional Knockout Mice.

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders characterized by deficits in social communication, social interaction, and the presence of restricted repetitive behaviors. The cause of ASD involves complex interactions between genetic and environmental factors. Haploinsufficiency of the Coiled-coil and C2 domain containing 1A (Cc2d1a) gene is causally linked to ASD, and obesity has been associated with worse outcomes for ASD. High-fat diet (HFD) feeding leads to the development of obesity and metabolic dysfunction; however, the effect of HFD on pre-existing autistic-like phenotypes remains to be clarified. Here, we report that male Cc2d1a conditional knockout (cKO) mice fed with HFD, from weaning onwards and throughout the experimental period, show a marked aggravation in autistic-like phenotypes, manifested in increased restricted repetitive behaviors and impaired performance in the preference for social novelty, but not in sociability and cognitive impairments assessed using the object location memory, novel object recognition, and Morris water maze tests. HFD feeding also results in increased numbers of reactive microglia and astrocytes, and exacerbates reductions in dendritic complexity and spine density of hippocampal CA1 pyramidal neurons. Furthermore, we demonstrate that chronic treatment with minocycline, a semisynthetic tetracycline-derived antibiotic, rescues the observed behavioral and morphological deficits in Cc2d1a cKO mice fed with HFD. Collectively, these findings highlight an aggravating role of HFD in pre-existing autistic-like phenotypes and suggest that minocycline treatment can alleviate abnormal neuronal morphology and behavioral symptoms associated with ASD resulted from the interplay between genetic and environmental risk factors.

A hybrid with distributed pooling blockchain protocol for image storage.

As a distributed storage scheme, the blockchain network lacks storage space has been a long-term concern in this field. At present, there are relatively few research on algorithms and protocols to reduce the storage requirement of blockchain, and the existing research has limitations such as sacrificing fault tolerance performance and raising time cost, which need to be further improved. Facing the above problems, this paper proposes a protocol based on Distributed Image Storage Protocol (DISP), which can effectively improve blockchain storage space and reduces computational costs in the help of InterPlanetary File System (IPFS). In order to prove the feasibility of the protocol, we make full use of IPFS and distributed database to design a simulation experiment for blockchain. Through distributed pooling (DP) algorithm in this protocol, we can divide image evidence into recognizable several small files and stored in several nodes. And these files can be restored to lossless original documents again by inverse distributed pooling (IDP) algorithm after authorization. These advantages in performance create conditions for large scale industrial and commercial applications.

Exploring the COVID-19 Pandemic as a Catalyst for Behavior Change Among Patient Health Record App Users in Taiwan: Development and Usability Study.

BACKGROUND: During the COVID-19 pandemic, personal health records (PHRs) have enabled patients to monitor and manage their medical data without visiting hospitals and, consequently, minimize their infection risk. Taiwan's National Health Insurance Administration (NHIA) launched the My Health Bank (MHB) service, a national PHR system through which insured individuals to access their cross-hospital medical data. Furthermore, in 2019, the NHIA released the MHB software development kit (SDK), which enables development of mobile apps with which insured individuals can retrieve their MHB data. However, the NHIA MHB service has its limitations, and the participation rate among insured individuals is low. OBJECTIVE: We aimed to integrate the MHB SDK with our developed blockchain-enabled PHR mobile app, which enables patients to access, store, and manage their cross-hospital PHR data. We also collected and analyzed the app's log data to examine patients' MHB use during the COVID-19 pandemic. METHODS: We integrated our existing blockchain-enabled mobile app with the MHB SDK to enable NHIA MHB data retrieval. The app utilizes blockchain technology to encrypt the downloaded NHIA MHB data. Existing and new indexes can be synchronized between the app and blockchain nodes, and high security can be achieved for PHR management. Finally, we analyzed the app's access logs to compare patients' activities during high and low COVID-19 infection periods. RESULTS: We successfully integrated the MHB SDK into our mobile app, thereby enabling patients to retrieve their cross-hospital medical data, particularly those related to COVID-19 rapid and polymerase chain reaction testing and vaccination information and progress. We retrospectively collected the app's log data for the period of July 2019 to June 2021. From January 2020, the preliminary results revealed a steady increase in the number of people who applied to create a blockchain account for access to their medical data and the number of app subscribers among patients who visited the outpatient department (OPD) and emergency department (ED). Notably, for patients who visited the OPD and ED, the peak proportions with respect to the use of the app for OPD and ED notes and laboratory test results also increased year by year. The highest proportions were 52.40% for ED notes in June 2021, 88.10% for ED laboratory test reports in May 2021, 34.61% for OPD notes in June 2021, and 41.87% for OPD laboratory test reports in June 2021. These peaks coincided with Taiwan's local COVID-19 outbreak lasting from May to June 2021. CONCLUSIONS: This study developed a blockchain-enabled mobile app, which can periodically retrieve and integrate PHRs from the NHIA MHB's cross-hospital data and the investigated hospital's self-pay medical data. Analysis of users' access logs revealed that the COVID-19 pandemic substantially increased individuals' use of PHRs and their health awareness with respect to COVID-19 prevention.

Loss of CC2D1A in Glutamatergic Neurons Results in Autistic-Like Features in Mice.

Biallelic loss-of-function mutations in Coiled-coil and C2 domain containing 1A (CC2D1A) cause autosomal recessive intellectual disability, sometimes comorbid with other neurodevelopmental disabilities, such as autism spectrum disorder (ASD) and seizures. We recently reported that conditional deletion of Cc2d1a in glutamatergic neurons of the postnatal mouse forebrain leads to impaired hippocampal synaptic plasticity and cognitive function. However, the pathogenic origin of the autistic features of CC2D1A deficiency remains elusive. Here, we confirmed that CC2D1A is highly expressed in the cortical zones during embryonic development. Taking advantage of Cre-LoxP-mediated gene deletion strategy, we generated a novel line of Cc2d1a conditional knockout (cKO) mice by crossing floxed Cc2d1a mice with Emx1-Cre mice, in which CC2D1A is ablated specifically in glutamatergic neurons throughout all embryonic and adult stages. We found that CC2D1A deletion leads to a trend toward decreased number of cortical progenitor cells at embryonic day 12.5 and alters the cortical thickness on postnatal day 10. In addition, male Cc2d1a cKO mice display autistic-like phenotypes including self-injurious repetitive grooming and aberrant social interactions. Loss of CC2D1A also results in decreased complexity of apical dendritic arbors of medial prefrontal cortex (mPFC) layer V pyramidal neurons and increased synaptic excitation/inhibition (E/I) ratio in the mPFC. Notably, chronic treatment with minocycline rescues behavioral and morphological abnormalities, as well as E/I changes, in male Cc2d1a cKO mice. Together, these findings indicate that male Cc2d1a cKO mice recapitulate autistic-like phenotypes of human disorder and suggest that minocycline has both structural and functional benefits in treating ASD.

Blockchain-Enabled iWellChain Framework Integration With the National Medical Referral System: Development and Usability Study.

BACKGROUND: Medical referral is the transfer of a patient's care from one physician to another upon request. This process involves multiple steps that require provider-to-provider and provider-to-patient communication. In Taiwan, the National Health Insurance Administration (NHIA) has implemented a national medical referral (NMR) system, which encourages physicians to refer their patients to different health care facilities to reduce unnecessary hospital visits and the financial stress on the national health insurance. However, the NHIA's NMR system is a government-based electronic medical referral service, and its referral data access and exchange are limited to authorized clinical professionals using their national health smart cards over the NHIA virtual private network. Therefore, this system lacks scalability and flexibility and cannot establish trusting relationships among patients, family doctors, and specialists. OBJECTIVE: To eliminate the existing restrictions of the NHIA's NMR system, this study developed a scalable, flexible, and blockchain-enabled framework that leverages the NHIA's NMR referral data to build an alliance-based medical referral service connecting health care facilities. METHODS: We developed a blockchain-enabled framework that can integrate patient referral data from the NHIA's NMR system with electronic medical record (EMR) and electronic health record (EHR) data of hospitals and community-based clinics to establish an alliance-based medical referral service serving patients, clinics, and hospitals and improve the trust in relationships and transaction security. We also developed a blockchain-enabled personal health record decentralized app (DApp) based on our blockchain-enabled framework for patients to acquire their EMR and EHR data; DApp access logs were collected to assess patients' behavior and investigate the acceptance of our personal authorization-controlled framework. RESULTS: The constructed iWellChain Framework was installed in an affiliated teaching hospital and four collaborative clinics. The framework renders all medical referral processes automatic and paperless and facilitates efficient NHIA reimbursements. In addition, the blockchain-enabled iWellChain DApp was distributed for patients to access and control their EMR and EHR data. Analysis of 3 months (September to December 2018) of access logs revealed that patients were highly interested in acquiring health data, especially those of laboratory test reports. CONCLUSIONS: This study is a pioneer of blockchain applications for medical referral services, and the constructed framework and DApp have been applied practically in clinical settings. The iWellChain Framework has the scalability to deploy a blockchain environment effectively for health care facilities; the iWellChain DApp has potential for use with more patient-centered applications to collaborate with the industry and facilitate its adoption.

Authorship Correction: A Clinical Decision Support Engine Based on a National Medication Repository for the Detection of Potential Duplicate Medications: Design and Evaluation.

[This corrects the article DOI: 10.2196/medinform.9064.].

Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation.

Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionarily conserved protein, originally identified as a nuclear factor-κB activator through a large-scale screen of human genes. Mutations in the human Cc2d1a gene result in autosomal recessive nonsyndromic intellectual disability. It remains unclear, however, how Cc2d1a mutation leads to alterations in brain function. Here, we have taken advantage of Cre/loxP recombinase-based strategy to conditionally delete Cc2d1a exclusively from excitatory neurons of male mouse forebrain to examine its role in hippocampal synaptic plasticity and cognitive function. We confirmed the expression of CC2D1A protein and mRNA in the mouse hippocampus. Double immunofluorescence staining showed that CC2D1A is expressed in both excitatory and inhibitory neurons of the adult hippocampus. Conditional deletion of Cc2d1a (cKO) from excitatory neurons leads to impaired performance in object location memory test and altered anxiety-like behavior. Consistently, cKO mice displayed a deficit in the maintenance of LTP in the CA1 region of hippocampal slices. Cc2d1a deletion also resulted in decreased complexity of apical and basal dendritic arbors of CA1 pyramidal neurons. An enhanced basal Rac1 activity was observed following Cc2d1a deletion, and this enhancement was mediated by reduced SUMO-specific protease 1 (SENP1) and SENP3 expression, thus increasing the amount of Rac1 SUMOylation. Furthermore, partial blockade of Rac1 activity rescued impairments in LTP and object location memory performance in cKO mice. Together, our results implicate Rac1 hyperactivity in synaptic plasticity and cognitive deficits observed in Cc2d1a cKO mice and reveal a novel role for CC2D1A in regulating hippocampal synaptic function.SIGNIFICANCE STATEMENT CC2D1A is abundantly expressed in the brain, but there is little known about its physiological function. Taking advantage of Cc2d1a cKO mice, the present study highlights the importance of CC2D1A in the maintenance of LTP at Schaffer collateral-CA1 synapses and the formation of hippocampus-dependent long-term object location memory. Our findings establish a critical link between elevated Rac1 activity, structural and synaptic plasticity alterations, and cognitive impairment caused by Cc2d1a deletion. Moreover, partial blockade of Rac1 activity rescues synaptic plasticity and memory deficits in Cc2d1a cKO mice. Such insights may have implications for the utility of Rac1 inhibitors in the treatment of intellectual disability caused by Cc2d1a mutations in human patients.

Correction: Src and SHP2 coordinately regulate the dynamics and organization of vimentin filaments during cell migration.

The original version of this article contained error in Fig. 6b, where several panels were missing from the published version. The corrected version of this Figure now appears in the article.

Author Contribution Correction: An Integrated Influenza Surveillance Framework Based on National Influenza-Like Illness Incidence and Multiple Hospital Electronic Medical Records for Early Prediction of Influenza Epidemics: Design and Evaluation.

[This corrects the article DOI: 10.2196/12341.].

An Integrated Influenza Surveillance Framework Based on National Influenza-Like Illness Incidence and Multiple Hospital Electronic Medical Records for Early Prediction of Influenza Epidemics: Design and Evaluation.

BACKGROUND: Influenza is a leading cause of death worldwide and contributes to heavy economic losses to individuals and communities. Therefore, the early prediction of and interventions against influenza epidemics are crucial to reduce mortality and morbidity because of this disease. Similar to other countries, the Taiwan Centers for Disease Control and Prevention (TWCDC) has implemented influenza surveillance and reporting systems, which primarily rely on influenza-like illness (ILI) data reported by health care providers, for the early prediction of influenza epidemics. However, these surveillance and reporting systems show at least a 2-week delay in prediction, indicating the need for improvement. OBJECTIVE: We aimed to integrate the TWCDC ILI data with electronic medical records (EMRs) of multiple hospitals in Taiwan. Our ultimate goal was to develop a national influenza trend prediction and reporting tool more accurate and efficient than the current influenza surveillance and reporting systems. METHODS: First, the influenza expertise team at Taipei Medical University Health Care System (TMUHcS) identified surveillance variables relevant to the prediction of influenza epidemics. Second, we developed a framework for integrating the EMRs of multiple hospitals with the ILI data from the TWCDC website to proactively provide results of influenza epidemic monitoring to hospital infection control practitioners. Third, using the TWCDC ILI data as the gold standard for influenza reporting, we calculated Pearson correlation coefficients to measure the strength of the linear relationship between TMUHcS EMRs and regional and national TWCDC ILI data for 2 weekly time series datasets. Finally, we used the Moving Epidemic Method analyses to evaluate each surveillance variable for its predictive power for influenza epidemics. RESULTS: Using this framework, we collected the EMRs and TWCDC ILI data of the past 3 influenza seasons (October 2014 to September 2017). On the basis of the EMRs of multiple hospitals, 3 surveillance variables, TMUHcS-ILI, TMUHcS-rapid influenza laboratory tests with positive results (RITP), and TMUHcS-influenza medication use (IMU), which reflected patients with ILI, those with positive results from rapid influenza diagnostic tests, and those treated with antiviral drugs, respectively, showed strong correlations with the TWCDC regional and national ILI data (r=.86-.98). The 2 surveillance variables-TMUHcS-RITP and TMUHcS-IMU-showed predictive power for influenza epidemics 3 to 4 weeks before the increase noted in the TWCDC ILI reports. CONCLUSIONS: Our framework periodically integrated and compared surveillance data from multiple hospitals and the TWCDC website to maintain a certain prediction quality and proactively provide monitored results. Our results can be extended to other infectious diseases, mitigating the time and effort required for data collection and analysis. Furthermore, this approach may be developed as a cost-effective electronic surveillance tool for the early and accurate prediction of epidemics of influenza and other infectious diseases in densely populated regions and nations.

Src and SHP2 coordinately regulate the dynamics and organization of vimentin filaments during cell migration.

Vimentin intermediate filaments (VIFs), expressed in most mesenchymal and cancer cells, undergo dramatic reorganization during cell migration; however, the mechanism remains obscure. This study demonstrates that upon growth-factor stimulation, Src directly phosphorylates vimentin at Tyr117, leading to VIF disassembly into squiggles and particles at the cell edge during lamellipodia formation. The protein tyrosine phosphatase SHP2 counteracted the Src effects on VIF tyrosine phosphorylation and organization. VIFs formed by vimentin Y117D mutant were more soluble and dynamic than those formed by the wild-type and Y117F mutant. Increased expression of vimentin promoted growth-factor induced lamellipodia formation and cell migration, whereas the mutants suppressed both. The vimentin-induced increase in lamellipodia formation correlated with the activation of Rac and Vav2, with the latter associated with VIFs and recruited to the plasma membrane upon growth-factor stimulation. These results reveal a novel mechanism for regulating VIF dynamics through Src and SHP2 and demonstrate that proper VIF dynamics are important for Rac activation and cell migration.

A Clinical Decision Support Engine Based on a National Medication Repository for the Detection of Potential Duplicate Medications: Design and Evaluation.

BACKGROUND: A computerized physician order entry (CPOE) system combined with a clinical decision support system can reduce duplication of medications and thus adverse drug reactions. However, without infrastructure that supports patients' integrated medication history across health care facilities nationwide, duplication of medication can still occur. In Taiwan, the National Health Insurance Administration has implemented a national medication repository and Web-based query system known as the PharmaCloud, which allows physicians to access their patients' medication records prescribed by different health care facilities across Taiwan. OBJECTIVE: This study aimed to develop a scalable, flexible, and thematic design-based clinical decision support (CDS) engine, which integrates a national medication repository to support CPOE systems in the detection of potential duplication of medication across health care facilities, as well as to analyze its impact on clinical encounters. METHODS: A CDS engine was developed that can download patients' up-to-date medication history from the PharmaCloud and support a CPOE system in the detection of potential duplicate medications. When prescribing a medication order using the CPOE system, a physician receives an alert if there is a potential duplicate medication. To investigate the impact of the CDS engine on clinical encounters in outpatient services, a clinical encounter log was created to collect information about time, prescribed drugs, and physicians' responses to handling the alerts for each encounter. RESULTS: The CDS engine was installed in a teaching affiliate hospital, and the clinical encounter log collected information for 3 months, during which a total of 178,300 prescriptions were prescribed in the outpatient departments. In all, 43,844/178,300 (24.59%) patients signed the PharmaCloud consent form allowing their physicians to access their medication history in the PharmaCloud. The rate of duplicate medication was 5.83% (1843/31,614) of prescriptions. When prescribing using the CDS engine, the median encounter time was 4.3 (IQR 2.3-7.3) min, longer than that without using the CDS engine (median 3.6, IQR 2.0-6.3 min). From the physicians' responses, we found that 42.06% (1908/4536) of the potential duplicate medications were recognized by the physicians and the medication orders were canceled. CONCLUSIONS: The CDS engine could easily extend functions for detection of adverse drug reactions when more and more electronic health record systems are adopted. Moreover, the CDS engine can retrieve more updated and completed medication histories in the PharmaCloud, so it can have better performance for detection of duplicate medications. Although our CDS engine approach could enhance medication safety, it would make for a longer encounter time. This problem can be mitigated by careful evaluation of adopted solutions for implementation of the CDS engine. The successful key component of a CDS engine is the completeness of the patient's medication history, thus further research to assess the factors in increasing the PharmaCloud consent rate is required.

Conditional deletion of Eps8 reduces hippocampal synaptic plasticity and impairs cognitive function.

Epidermal growth factor receptor substrate 8 (Eps8) is a multifunctional protein involved in actin cytoskeleton regulation and is abundantly expressed in many brain regions. However, the functional significance of Eps8 in the brain has only just begun to be elucidated. Here, we demonstrate that genetic deletion of Eps8 (Eps8-/-) from excitatory neurons leads to impaired performance in a novel object recognition test. Consistently, Eps8-/- mice displayed a deficit in the maintenance of long-term potentiation in the CA1 region of hippocampal slices, which was rescued by bath application of N-methyl-d-aspartate receptor (NMDAR) antagonist 2-amino-5-phosphonopentanoate. While Eps8-/- mice showed normal basal synaptic transmission, a significant increase in the amplitude and a significantly slower decay kinetic of NMDAR-mediated excitatory postsynaptic currents (EPSCs) were observed in hippocampal CA1 neurons. Furthermore, a significant increase in the expression of ifenprodil-sensitive NMDAR-mediated EPSCs was observed in neurons from Eps8-/- mice compared with those from wild-type mice. Eps8 deletion led to decreased mature mushroom-shaped dendritic spine density but increased complexity of basal dendritic trees of hippocampal CA1 pyramidal neurons. These results implicate NMDAR hyperfunction in the cognitive deficits observed in Eps8-/- mice and demonstrate a novel role for Eps8 in regulating hippocampal long-term synaptic plasticity and cognitive function. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.