Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption.

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.

Social anxiety and loneliness among older adults: a moderated mediation model.

BACKGROUND: Few studies have clarified the mechanisms linking social anxiety and loneliness in older populations. The study aimed to explore how social network mediate the relationship between social anxiety and loneliness in older adults, with perceived social support playing a moderating role. METHODS: A total of 454 older patients completed the Social Avoidance and Distress Scale, Lubben Social Network Scale-6, Chinese version of the Short Loneliness Scale and Perceived Social Support Scale. Bootstrap and simple slope methods were used to test the moderated mediation model. RESULTS: Social anxiety had a significant positive predictive effect on loneliness and social network partially mediated this relationship. The relationship between social anxiety and social network, as well as the relationship between social network and loneliness, was moderated by perceived social support. Specifically, perceived social support buffered the effects of social anxiety on social network, but the buffering effect diminished with increasing levels of social anxiety. On the social network and loneliness pathway, the social network of older persons with higher perceived social support has a stronger prediction of loneliness. CONCLUSIONS: The study found that social anxiety can contribute to loneliness by narrowing older adults' social network. High perceived social support can buffer this process, but do not overstate its protective effects. Thus, interventions to reduce social anxiety and improve social network and social support may help prevent and alleviate loneliness in older adults.

Real-Time Impedance-Based Monitoring of the Growth and Inhibition of Osteomyelitis Biofilm Pathogen Staphylococcus aureus Treated with Novel Bisphosphonate-Fluoroquinolone Antimicrobial Conjugates.

Osteomyelitis is a limb- and life-threatening orthopedic infection predominantly caused by Staphylococcus aureus biofilms. Bone infections are extremely challenging to treat clinically. Therefore, we have been designing, synthesizing, and testing novel antibiotic conjugates to target bone infections. This class of conjugates comprises bone-binding bisphosphonates as biochemical vectors for the delivery of antibiotic agents to bone minerals (hydroxyapatite). In the present study, we utilized a real-time impedance-based assay to study the growth of Staphylococcus aureus biofilms over time and to test the antimicrobial efficacy of our novel conjugates on the inhibition of biofilm growth in the presence and absence of hydroxyapatite. We tested early and newer generation quinolone antibiotics (ciprofloxacin, moxifloxacin, sitafloxacin, and nemonoxacin) and several bisphosphonate-conjugated versions of these antibiotics (bisphosphonate-carbamate-sitafloxacin (BCS), bisphosphonate-carbamate-nemonoxacin (BCN), etidronate-carbamate-ciprofloxacin (ECC), and etidronate-carbamate-moxifloxacin (ECX)) and found that they were able to inhibit Staphylococcus aureus biofilms in a dose-dependent manner. Among the conjugates, the greatest antimicrobial efficacy was observed for BCN with an MIC of 1.48 µg/mL. The conjugates demonstrated varying antimicrobial activity depending on the specific antibiotic used for conjugation, the type of bisphosphonate moiety, the chemical conjugation scheme, and the presence or absence of hydroxyapatite. The conjugates designed and tested in this study retained the bone-binding properties of the parent bisphosphonate moiety as confirmed using high-performance liquid chromatography. They also retained the antimicrobial activity of the parent antibiotic in the presence or absence of hydroxyapatite, albeit at lower levels due to the nature of their chemical modification. These findings will aid in the optimization and testing of this novel class of drugs for future applications to pharmacotherapy in osteomyelitis.

Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine.

A bone imaging toolkit of 21 fluorescent probes with variable spectroscopic properties, bone mineral binding affinities, and antiprenylation activities has been created, including a novel linking strategy. The linking chemistry allows attachment of a diverse selection of dyes fluorescent in the visible to near-infrared range to any of the three clinically important heterocyclic bisphosphonate bone drugs (risedronate, zoledronate, and minodronate or their analogues). The resultant suite of conjugates offers multiple options to "mix and match" parent drug structure, fluorescence emission wavelength, relative bone affinity, and presence or absence of antiprenylation activity, for bone-related imaging applications.

Bisphosphonate uptake in areas of tooth extraction or periapical disease.

PURPOSE: Bisphosphonates (BPs) are widely used for the management of bone diseases such as osteoporosis and bone malignancy. However, osteonecrosis of the jaws (ONJ) is a serious complication of BP treatment. ONJ lesions mainly occur after extraction of teeth deemed unrestorable or around teeth with active periodontal or periapical disease. Because socket healing or dental disease shows higher bone turnover, the authors hypothesized that preferentially high BP accumulation would be observed in these areas. MATERIALS AND METHODS: The authors tested the uptake of fluorescein-labeled zoledronic acid (5-FAM-ZOL) in sites of tooth extraction or experimental periapical disease in mice. Maxillary molars were extracted or the crowns of mandibular molars were drilled to induce pulp exposure. Animals were injected with 5-FAM-ZOL 200 µg/kg at various times after intervention and fluorescence was measured at healthy versus intervention sites. Fluorescein injections were used as controls. Data were analyzed by t test and mixed effects linear models were constructed because the animals had repeated measurements over time and at the 2 sites. RESULTS: A statistically significant (P≤.001 to .002) time-dependent uptake of 5-FAM-ZOL was detected in the areas of extraction socket and in the alveolar ridge around teeth with periapical disease compared with the healthy contralateral sites of the same animals. For the 2 conditions, the uptake reached a maximum 3 days after experimental intervention and decreased thereafter. CONCLUSIONS: These data suggest that sites with increased bone turnover, such as extraction sites or areas of periapical inflammation, are exposed to higher BP doses than the remaining alveolar ridge and could explain, at least in part, the susceptibility of such areas to ONJ.

Alkali-Ion Intercalation Chemistry and Phase Evolution of Sn4P3.

Despite its high theoretical capacities, Sn4P3 anodes in alkali-ion batteries (AIBs) have been plagued by electrode damage and capacity decay during cycling, mainly rooted in the huge volume changes and irreversible phase segregation. However, few reports endeavor to ascertain whether these causes bear relevance to phase evolution upon cycling. Moreover, the phase evolution mechanism for alkali-ion intercalation remains imprecise. Herein, the structural transformations and detailed mechanisms upon various alkali-ion intercalation processes are systematically revealed, utilizing both experimental techniques and theoretical simulations. The results reveal that the energy storage of Sn4P3 occurs in a two-stage process, starting from an insertion process, followed by a transition process. As the cycle proceeds, the final delithiated/desodiated/depotassiated components gradually trap alkali ions (Li+, Na+, and K+), which is attributed to the incomplete electrochemical transition and difficulty in Sn4P3 regeneration due to the kinetic limitations in removing M (M = Li, Na, and K). Furthermore, Sn4P3 anode obeys the "shrinking core mechanism" in potassium-ion batteries (KIBs), wherein a minor fraction of Sn4P3 in the outer layer of the particles is initially involved in the potassiation/depotassiation processes, followed by a gradual participation of the inner parts until the entire particle is involved. It is worth mentioning that K-Sn alloys are not found to exist during the transition process of KIBs; instead, K-Sn-P phases are found, which makes it differ from that in lithium-ion batteries (LIBs) and sodium-ion batteries (NIBs). These findings are expected to deepen the understanding of the reaction mechanism of Sn4P3 and enlighten the material designs for improved performance.

Resting-state dynamic functional connectivity in major depressive disorder: A systematic review.

As a novel measure, dynamic functional connectivity (dFC) provides insight into the dynamic nature of brain networks and their interactions in resting-state, surpassing traditional static functional connectivity in pathological conditions such as depression. Since a comprehensive review is still lacking, we then reviewed forty-five eligible papers to explore pathological mechanisms of major depressive disorder (MDD) from perspectives including abnormal brain regions and functional networks, brain state, topological properties, relevant recognition, along with longitudinal studies. Though inconsistencies could be found, common findings are: (1) From different perspectives based on dFC, default-mode network (DMN) with its subregions exhibited a close relation to the pathological mechanism of MDD. (2) With a corrupted integrity within large-scale functional networks and imbalance between them, longer fraction time in a relatively weakly-connected state may be a possible property of MDD concerning its relation with DMN. Abnormal transition frequencies between states were correlated to the severity of MDD. (3) Including dynamic properties in topological network metrics enhanced recognition effect. In all, this review summarized its use for clinical diagnosis and treatment, elucidating the non-stationary of MDD patients' aberrant brain activity in the absence of stimuli and bringing new views into its underlying neuro mechanism.

Analysis of functional connectivity in depression based on a weighted hyper-network method.

Objective. Brain connectivity network is a vital tool to reveal the interaction between different brain regions. Currently, most functional connectivity methods can only capture pairs of information to construct brain networks which ignored the high-order correlations between brain regions.Approach. Therefore, this study proposed a weighted connectivity hyper-network based on resting-state EEG data, and then applied to depression identification and analysis. The hyper-network model was build based on least absolute shrinkage and selection operator sparse regression method to effectively represent the higher-order relationships of brain regions. On this basis, by integrating the correlation-based weighted hyper-edge information, the weighted hyper-network is constructed, and the topological features of the network are extracted for classification.Main results. The experimental results obtained an optimal accuracy compared to the traditional coupling methods. The statistical results on network metrics proved that there were significant differences between depressive patients and normal controls. In addition, some brain regions and electrodes were found and discussed to highly correlate with depression by analyzing of the critical nodes and hyper-edges.Significance. These may help discover disease-related biomarkers important for depression diagnosis.

Risk Prediction of Alzheimer's Disease Conversion in Mild Cognitive Impaired Population Based on Brain Age Estimation.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the world. To reduce the incidence of AD, it's essential to quantify the AD conversion risk of mild cognitive impaired (MCI) individuals. Here, we propose an AD conversion risk estimation system (CRES), which contains an automated MRI feature extractor, brain age estimation (BAE) module, and AD conversion risk estimation module. The CRES is trained on 634 normal controls (NC) from the public IXI and OASIS cohorts, then it is evaluated on 462 subjects (106 NC, 102 stable MCI (sMCI), 124 progressive MCI (pMCI) and 130 AD) from the ADNI dataset. Experimental results show that the MRI derived age gap (AG, chronological age subtracted from the estimated brain age) significantly distinguish NC, sMCI, pMCI and AD groups with p -value =0.000017 . Considering AG as the primary factor, incorporating gender and Minimum Mental State Examination (MMSE) for more robust Cox multi-variate hazard analysis, we concluded that each additional year in AG is associated with 4.57% greater AD conversion risk for the MCI group. Furthermore, a nomogram was drawn to describe MCI conversion risk at the individual level in the next 1 year, 3 years, 5 years and even 8 years from baseline. This work demonstrates that CRES can estimate AG based on MRI data, evaluate AD conversion risk of the MCI subjects, and identify the individuals with high AD conversion risk, which is valuable for effective intervention and diagnosis within an early period.

Clustering-Fusion Feature Selection Method in Identifying Major Depressive Disorder Based on Resting State EEG Signals.

Depression is a heterogeneous syndrome with certain individual differences among subjects. Exploring a feature selection method that can effectively mine the commonness intra-groups and the differences inter-groups in depression recognition is therefore of great significance. This study proposed a new clustering-fusion feature selection method. Hierarchical clustering (HC) algorithm was used to capture the heterogeneity distribution of subjects. Average and similarity network fusion (SNF) algorithms were adopted to characterize the brain network atlas of different populations. Differences analysis was also utilized to obtain the features with discriminant performance. Experiments showed that compared with traditional feature selection methods, HCSNF method yielded the optimal classification results of depression recognition in both sensor and source layers of electroencephalography (EEG) data. Especially in the beta band of EEG data at sensor layer, the classification performance was improved by more than 6%. Moreover, the long-distance connections between parietal-occipital lobe and other brain regions not only have high discriminative power, but also significantly correlate with depressive symptoms, indicating the important role of these features in depression recognition. Therefore, this study may provide methodological guidance for the discovery of reproducible electrophysiological biomarkers and new insights into common neuropathological mechanisms of heterogeneous depression diseases.

How does Music Affect Your Brain? A Pilot Study on EEG and Music Features for Automatic Analysis.

Music can effectively induce specific emotion and usually be used in clinical treatment or intervention. The electroencephalogram can help reflect the impact of music. Previous studies showed that the existing methods achieved relatively good performance in predicting emotion response to music. However, these methods tend to be time consuming and expensive due to their complexity. To this end, this study proposes a grey wolf optimiser-based method to predict the induced emotion through fusing electroencephalogram features and music features. Experimental results show that, the proposed method can reach a promising performance for predicting emotional response to music and outperform the alternative method. In addition, we analyse the relationship between the music features and electroencephalogram features and the results demonstrate that, musical timbre features are significantly related to the electroencephalogram features.Clinical relevance- This study targets the automatic prediction of the human response to music. It further explores the correlation between EEG features and music features aiming to provide the basis for the extension to the application of music. The grey wolf optimiser-based method proposed in this study could supply a promising avenue for the emotion prediction as induced by music.

Brain function changes reveal rapid antidepressant effects of nitrous oxide for treatment-resistant depression:Evidence from task-state EEG.

Nitrous oxide has rapid antidepressant effects in patients with treatment-resistant depression (TRD), but its underlying mechanisms of therapeutic actions are not well understood. Moreover, most of the current studies lack objective biological indicators to evaluate the changes of nitrous oxide-induced brain function for TRD. Therefore, this study assessed the effect of nitrous oxide on brain function for TRD based on event-related potential (ERP) components and functional connectivity networks (FCNs) methods. In this randomized, longitudinal, placebo-controlled trial, all TRD participants were divided into two groups to receive either a 1-hour inhalation of nitrous oxide or a placebo treatment, and they took part in the same task-state electroencephalogram (EEG) experiment before and after treatment. The experimental results showed that nitrous oxide improved depressive symptoms better than placebo in terms of 17-Hamilton Depression Rating Scale score (HAMD-17). Statistical analysis based on ERP components showed that nitrous oxide-induced significant differences in amplitude and latency of N1, P1, N2, P2. In addition, increased brain functional connectivity was found after nitrous oxide treatment. And the change of network metrics has a significant correlation with decreased depressive symptoms. These findings may suggest that nitrous oxide improves depression symptoms for TRD by modifying brain function.

Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis.

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

Evidence of Bisphosphonate-Conjugated Sitafloxacin Eradication of Established Methicillin-Resistant S. aureus Infection with Osseointegration in Murine Models of Implant-Associated Osteomyelitis.

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (bisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy, while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

Bisphosphonate binding affinity affects drug distribution in both intracortical and trabecular bone of rabbits.

Differences in the binding affinities of bisphosphonates for bone mineral have been proposed to determine their localizations and duration of action within bone. The main objective of this study was to test the hypothesis that mineral binding affinity affects bisphosphonate distribution at the basic multicellular unit (BMU) level within both cortical and cancellous bone. To accomplish this objective, skeletally mature female rabbits (n = 8) were injected simultaneously with both low- and high-affinity bisphosphonate analogs bound to different fluorophores. Skeletal distribution was assessed in the rib, tibia, and vertebra using confocal microscopy. The staining intensity ratio between osteocytes contained within the cement line of newly formed rib osteons or within the reversal line of hemiosteons in vertebral trabeculae compared to osteocytes outside the cement/reversal line was greater for the high-affinity compared to the low-affinity compound. This indicates that the low-affinity compound distributes more equally across the cement/reversal line compared to a high-affinity compound, which concentrates mostly near surfaces. These data, from an animal model that undergoes intracortical remodeling similar to humans, demonstrate that the affinity of bisphosphonates for the bone determines the reach of the drugs in both cortical and cancellous bone.

Electroconvulsive Therapy-Induced Changes in Functional Brain Network of Major Depressive Disorder Patients: A Longitudinal Resting-State Electroencephalography Study.

Objectives: Several studies have shown abnormal network topology in patients with major depressive disorder (MDD). However, changes in functional brain networks associated with electroconvulsive therapy (ECT) remission based on electroencephalography (EEG) signals have yet to be investigated. Methods: Nineteen-channel resting-state eyes-closed EEG signals were collected from 24 MDD patients pre- and post-ECT treatment. Functional brain networks were constructed by using various coupling methods and binarization techniques. Changes in functional connectivity and network metrics after ECT treatment and relationships between network metrics and clinical symptoms were explored. Results: ECT significantly increased global efficiency, edge betweenness centrality, local efficiency, and mean degree of alpha band after ECT treatment, and an increase in these network metrics had significant correlations with decreased depressive symptoms in repeated measures correlation. In addition, ECT regulated the distribution of hubs in frontal and occipital lobes. Conclusion: ECT modulated the brain's global and local information-processing patterns. In addition, an ECT-induced increase in network metrics was associated with clinical remission. Significance: These findings might present the evidence for us to understand how ECT regulated the topology organization in functional brain networks of clinically remitted depressive patients.

Abnormal Brain Topological Structure of Mild Depression During Visual Search Processing Based on EEG Signals.

Studies have shown that attention bias can affect behavioral indicators in patients with depression, but it is still unclear how this bias affects the brain network topology of patients with mild depression (MD). Therefore, a novel functional brain network analysis and hierarchical clustering methods were used to explore the abnormal brain topology of MD patients based on EEG signals during the visual search paradigm. The behavior results showed that the reaction time of MD group was significantly higher than that of normal group. The results of functional brain network indicated significant differences in functional connections between the two groups, the amount of inter-hemispheric long-distance connections are much larger than intra-hemispheric short-distance connections. Patients with MD showed significantly lower local efficiency and clustering coefficient, destroyed community structure of frontal lobe and parietal-occipital lobe, frontal asymmetry, especially in beta band. In addition, the average value of long-distance connections between left frontal and right parietal-occipital lobes presented significant correlation with depressive symptoms. Our results suggested that MD patients achieved long-distance connections between the frontal and parietal-occipital regions by sacrificing the connections within the regions, which might provide new insights into the abnormal cognitive processing mechanism of depression.

Health literacy and health outcomes among older patients suffering from chronic diseases: A moderated mediation model.

Introduction: Aging brings with an increased risk of chronic diseases among older adults, which could affect health outcomes. Evidence has showed that health literacy is associated with health outcomes. However, limited studies explore the underlying mechanism between health literacy and health outcomes. Hence, this study aimed to determine whether self-efficacy for managing chronic disease mediates the relationship between health literacy and health outcomes among older patients with chronic diseases, and to explore whether disease duration moderates the relationship between health literacy, self-efficacy for managing chronic disease, and health outcomes. Methods: Participants were recruited from tertiary hospitals in Zhejiang Province, China from May 2019 to June 2020 using a convenience sampling method. A total of 471 older patients with chronic diseases completed questionnaires measuring demographics, disease-related information, health literacy, self-efficacy for managing chronic disease, and health outcomes. The mediation effect was examined using the structural equation model method, based on the bias-corrected bootstrapping method. The moderation effect was tested by the multiple-group analysis. Results: A good fit model suggested that self-efficacy for managing chronic disease partially mediated the relationships between health literacy and health outcomes. In addition, disease duration moderated the relationships between health literacy, self-efficacy for managing chronic disease, and health outcomes. Discussion: The findings highlight that adequate health literacy improved health outcomes among older patients with chronic diseases, which was further promoted by self-efficacy for managing chronic diseases. Moreover, a long disease duration could enhance the effect.

Gender differences in factors associated with the health literacy of hospitalized older patients with chronic diseases: A cross-sectional study.

Background: To identify gender differences in factors associated with the health literacy of hospitalized older patients with chronic diseases. Methods: A total of 471 hospitalized older patients with chronic diseases in four hospitals were investigated from May 2019 to June 2020. The self-developed demographic information questionnaire, the "Health Literacy Scale for Patients with Chronic Diseases" and the "Self-Efficacy for Managing Chronic Diseases 6-item Scale" were applied in this study. Multiple linear regression was used to assess the factors influencing health literacy among older patients with chronic diseases by gender. Results: The factors influencing health literacy differed by gender. Male health literacy was related to education background, number of children, monthly income, duration of chronic disease and chronic disease self-efficacy. For females, health literacy was associated with age, education background, monthly income, duration of chronic disease and chronic disease treatment. Conclusion: Healthcare providers should focus on the above-mentioned factors that could help identify those with low health literacy differ base on gender. Gender-specific strategies should be developed to improve the health literacy of older patients with chronic diseases and strengthen their chronic disease management.