Integrity of neural extracellular matrix is required for microglia-mediated synaptic remodeling.

Microglia continuously remodel synapses, which are embedded in the extracellular matrix (ECM). However, the mechanisms, which govern this process remain elusive. To investigate the influence of the neural ECM in synaptic remodeling by microglia, we disrupted ECM integrity by injection of chondroitinase ABC (ChABC) into the retrosplenial cortex of healthy adult mice. Using in vivo two-photon microscopy we found that ChABC treatment increased microglial branching complexity and ECM phagocytic capacity and decreased spine elimination rate under basal conditions. Moreover, ECM attenuation largely prevented synaptic remodeling following synaptic stress induced by photodamage of single synaptic elements. These changes were associated with less stable and smaller microglial contacts at the synaptic damage sites, diminished deposition of calreticulin and complement proteins C1q and C3 at synapses and impaired expression of microglial CR3 receptor. Thus, our findings provide novel insights into the function of the neural ECM in deposition of complement proteins and synaptic remodeling by microglia.

Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments.

Dysregulated cortical expression of the neural cell adhesion molecule (NCAM) and deficits of its associated polysialic acid (polySia) have been found in Alzheimer's disease and schizophrenia. However, the functional role of polySia in cortical synaptic plasticity remains poorly understood. Here, we show that acute enzymatic removal of polySia in medial prefrontal cortex (mPFC) slices leads to increased transmission mediated by the GluN1/GluN2B subtype of N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-mediated extrasynaptic tonic currents, and impaired long-term potentiation (LTP). The latter could be fully rescued by pharmacological suppression of GluN1/GluN2B receptors, or by application of short soluble polySia fragments that inhibited opening of GluN1/GluN2B channels. These treatments and augmentation of synaptic NMDARs with the glycine transporter type 1 (GlyT1) inhibitor sarcosine also restored LTP in mice deficient in polysialyltransferase ST8SIA4. Furthermore, the impaired performance of polySia-deficient mice and two models of Alzheimer's disease in the mPFC-dependent cognitive tasks could be rescued by intranasal administration of polySia fragments. Our data demonstrate the essential role of polySia-NCAM in the balancing of signaling through synaptic/extrasynaptic NMDARs in mPFC and highlight the therapeutic potential of short polySia fragments to restrain GluN1/GluN2B-mediated signaling.

Real-time mechanisms of exacerbated synaptic remodeling by microglia in acute models of systemic inflammation and tauopathy.

Remodeling of synapses by microglia is essential for synaptic plasticity in the brain. However, during neuroinflammation and neurodegenerative diseases, microglia can induce excessive synaptic loss, although the precise underlying mechanisms are unknown. To directly observe microglia-synapse interactions under inflammatory conditions, we performed in vivo two-photon time-lapse imaging of microglia-synapse interactions after bacterial lipopolysaccharide administration to model systemic inflammation, or after inoculation of Alzheimer's disease (AD) brain extracts to model disease-associated neuroinflammatory microglial response. Both treatments prolonged microglia-neuron contacts, decreased basal surveillance of synapses and promoted synaptic remodeling in response to synaptic stress induced by focal single-synapse photodamage. Spine elimination correlated with the expression of microglial complement system/phagocytic proteins and the occurrence of synaptic filopodia. Microglia were observed contacting spines, then stretching and phagocytosing spine head filopodia. Thus, in response to inflammatory stimuli microglia exacerbated spine remodeling through prolonged microglial contact and elimination of spines 'tagged' by synaptic filopodia.

Attenuation of the extracellular matrix restores microglial activity during the early stage of amyloidosis.

In the advanced stages of Alzheimer's disease (AD), microglia are transformed to an activated phenotype with thickened and retracted processes, migrate to the site of amyloid-beta (Aß) plaques, and proliferate. In the early stages of AD, it is still poorly understood whether the microglial function is altered and which factors may regulate these changes. Here, we focused on studying microglia in the retrosplenial cortex (RSC) in 3- to 4-month-old 5xFAD mice as a transgenic mouse model of AD. At this age, there are neither Aß plaques, nor activation of microglia, nor dysregulation in the expression of genes encoding major extracellular matrix (ECM) molecules or extracellular proteases in the RSC. Still, histochemical evaluation of the fine structure of neural ECM revealed increased levels of Wisteria floribunda agglutinin labeling in holes of perineuronal nets and changes in the perimeter of ECM barriers around the holes in 5xFAD mice. Two-photon vital microscopy demonstrated normal morphology and resting motility of microglia but strongly diminished number of microglial cells that migrated to the photolesion site in 5xFAD mice. Enzymatic digestion of ECM by chondroitinase ABC (ChABC) ameliorated this defect. Accordingly, the characterization of cell surface markers by flow cytometry demonstrated altered expression of microglial CD45. Moreover, ChABC treatment reduced the invasion of myeloid-derived mononuclear cells into the RSC of 5xFAD mice. Hence, the migration of both microglia and myeloid cells is altered during the early stages of amyloidosis and can be restored at least partially by the attenuation of the ECM.

Podocyte Integrin-ß3 and Activated Protein C Coordinately Restrict RhoA Signaling and Ameliorate Diabetic Nephropathy.

BACKGROUND: Diabetic nephropathy (dNP), now the leading cause of ESKD, lacks efficient therapies. Coagulation protease-dependent signaling modulates dNP, in part via the G protein-coupled, protease-activated receptors (PARs). Specifically, the cytoprotective protease-activated protein C (aPC) protects from dNP, but the mechanisms are not clear. METHODS: A combination of in vitro approaches and mouse models evaluated the role of aPC-integrin interaction and related signaling in dNP. RESULTS: The zymogen protein C and aPC bind to podocyte integrin-ß3, a subunit of integrin-αvß3. Deficiency of this integrin impairs thrombin-mediated generation of aPC on podocytes. The interaction of aPC with integrin-αvß3 induces transient binding of integrin-ß3 with G α13 and controls PAR-dependent RhoA signaling in podocytes. Binding of aPC to integrin-ß3via its RGD sequence is required for the temporal restriction of RhoA signaling in podocytes. In podocytes lacking integrin-ß3, aPC induces sustained RhoA activation, mimicking the effect of thrombin. In vivo, overexpression of wild-type aPC suppresses pathologic renal RhoA activation and protects against dNP. Disrupting the aPC-integrin-ß3 interaction by specifically deleting podocyte integrin-ß3 or by abolishing aPC's integrin-binding RGD sequence enhances RhoA signaling in mice with high aPC levels and abolishes aPC's nephroprotective effect. Pharmacologic inhibition of PAR1, the pivotal thrombin receptor, restricts RhoA activation and nephroprotects RGE-aPChigh and wild-type mice.Conclusions aPC-integrin-αvß3 acts as a rheostat, controlling PAR1-dependent RhoA activation in podocytes in diabetic nephropathy. These results identify integrin-αvß3 as an essential coreceptor for aPC that is required for nephroprotective aPC-PAR signaling in dNP.

Study protocol: a randomised controlled trial of a telephone delivered social wellbeing and engaged living (SWEL) psychological intervention for disengaged youth.

BACKGROUND: Internationally, from 12.2-23.4% of youth (aged 16-24 years) are not in employment, education or training (NEET). These disengaged youth are more likely to experience social exclusion, increased psychological distress and poor quality of life. Youth at risk of disengagement are less likely to access traditional support services, requiring development of innovative interventions. METHODS: The trial is a single blind, three arm, randomised controlled trial evaluating the effectiveness of a telephone delivered psychological intervention for disengaged youth (12-25 years). Participants will be randomised to receive either (i) SWEL, (ii) Befriending, or (iii) Single Session Psycho-Education. Therapy will be over an 8 week period with a minimum of four and maximum of eight sessions for the SWEL or Befriending conditions, or a single session for the Psycho-Education condition. Outcomes will be assessed at baseline and at 2, 8 and 14-month follow-up with the primary outcome being re-engagement in education, training or employment. DISCUSSION: This large, multi-site, randomised controlled trial will inform the delivery of services for young people at risk of disengaging from education or training. The provision of psychological therapy by telephone increases access by youth - especially those in rural and remote areas - both to the trial and the treatment, if adopted by services. The outcomes of this trial could have meaningful societal impact for a vulnerable population. It is expected that recruitment, intervention and retention will present challenges for the trial given the focus on disengaged youth. TRIAL REGISTRATION: ANZCTR, ACTRN12614001212640 , Registered 18 Nov 2014. Retrospectively registered. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the participating institutions. Results of the trial will be submitted for publication in peer reviewed journals and findings presented at scientific conferences and to key service providers and policy makers.

Psychological interventions for co-occurring depression and substance use disorders.

BACKGROUND: Comorbid depression and substance use disorders are common and have poorer outcomes than either disorder alone. While effective psychological treatments for depression or substance use disorders are available, relatively few randomised controlled trials (RCTs) have examined the efficacy of these treatments in people with these comorbid disorders. OBJECTIVES: To assess the efficacy of psychological interventions delivered alone or in combination with pharmacotherapy for people diagnosed with comorbid depression and substance use disorders. SEARCH METHODS: We searched the following databases up to February 2019: Cochrane Central Register of Controlled Trials, PubMed, Embase, CINAHL, Google Scholar and clinical trials registers. All systematic reviews identified, were handsearched for relevant articles. SELECTION CRITERIA: The review includes data from RCTs of psychological treatments for people diagnosed with comorbid depression and substance use disorders, using structured clinical interviews. Studies were included if some of the sample were experiencing another mental health disorder (e.g. anxiety); however, studies which required a third disorder as part of their inclusion criteria were not included. Studies were included if psychological interventions (with or without pharmacotherapy) were compared with no treatment, delayed treatment, treatment as usual or other psychological treatments. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Seven RCTs of psychological treatments with a total of 608 participants met inclusion criteria. All studies were published in the USA and predominately consisted of Caucasian samples. All studies compared different types of psychological treatments. Two studies compared Integrated Cognitive Behavioural Therapy (ICBT) with Twelve Step Facilitation (TSF), another two studies compared Interpersonal Psychotherapy for Depression (IPT-D) with other treatment (Brief Supportive Therapy (BST) or Psychoeducation). The other three studies compared different types or combinations of psychological treatments. No studies compared psychological interventions with no treatment or treatment as usual control conditions. The studies included a diverse range of participants (e.g. veterans, prisoners, community adults and adolescents). All studies were at high risk of performance bias, other main sources were selection, outcome detection and attrition bias. Due to heterogeneity between studies only two meta-analyses were conducted. The first meta-analysis focused on two studies (296 participants) comparing ICBT to TSF. Very low-quality evidence revealed that while the TSF group had lower depression scores than the ICBT group at post-treatment (mean difference (MD) 4.05, 95% confidence interval (CI) 1.43 to 6.66; 212 participants), there was no difference between groups in depression symptoms (MD 1.53, 95% CI -1.73 to 4.79; 181 participants) at six- to 12-month follow-up. At post-treatment there was no difference between groups in proportion of days abstinent (MD -2.84, 95% CI -8.04 to 2.35; 220 participants), however, the ICBT group had a greater proportion of days abstinent than the TSF group at the six- to 12-month follow-up (MD 10.76, 95% CI 3.10 to 18.42; 189 participants). There were no differences between the groups in treatment attendance (MD -1.27, 95% CI -6.10 to 3.56; 270 participants) or treatment retention (RR 0.95, 95% CI 0.72 to 1.25; 296 participants). The second meta-analysis was conducted with two studies (64 participants) comparing IPT-D with other treatment (Brief Supportive Psychotherapy/Psychoeducation). Very low-quality evidence indicated IPT-D resulted in significantly lower depressive symptoms at post-treatment (MD -0.54, 95% CI -1.04 to -0.04; 64 participants), but this effect was not maintained at three-month follow-up (MD 3.80, 95% CI -3.83 to 11.43) in the one study reporting follow-up outcomes (38 participants; IPT-D versus Psychoeducation). Substance use was examined separately in each study, due to heterogeneity in outcomes. Both studies found very low-quality evidence of no significant differences in substance use outcomes at post-treatment (percentage of days abstinent, IPD versus Brief Supportive Psychotherapy; MD -2.70, 95% CI -28.74 to 23.34; 26 participants) or at three-month follow-up (relative risk of relapse, IPT-D versus Psychoeducation; RR 0.67, 95% CI 0.30 to 1.50; 38 participants). There was also very low-quality evidence for no significant differences between groups in treatment retention (RR 1.00, 95% CI 0.81 to 1.23; 64 participants). No adverse events were reported in any study. AUTHORS' CONCLUSIONS: The conclusions of this review are limited due to the low number and very poor quality of included studies. No conclusions can be made about the efficacy of psychological interventions (delivered alone or in combination with pharmacotherapy) for the treatment of comorbid depression and substance use disorders, as they are yet to be compared with no treatment or treatment as usual in this population. In terms of differences between psychotherapies, although some significant effects were found, the effects were too inconsistent and small, and the evidence of too poor quality, to be of relevance to practice.

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.

The coagulation protease activated protein C (aPC) confers cytoprotective effects in various in vitro and in vivo disease models, including diabetic nephropathy. The nephroprotective effect may be related to antioxidant effects of aPC. However, the mechanism through which aPC may convey these antioxidant effects and the functional relevance of these properties remain unknown. Here, we show that endogenous and exogenous aPC prevents glomerular accumulation of oxidative stress markers and of the redox-regulating protein p66(Shc) in experimental diabetic nephropathy. These effects were predominately observed in podocytes. In vitro, aPC inhibited glucose-induced expression of p66(Shc) mRNA and protein in podocytes (via PAR-1 and PAR-3) and various endothelial cell lines, but not in glomerular endothelial cells. Treatment with aPC reversed glucose-induced hypomethylation and hyperacetylation of the p66(Shc) promoter in podocytes. The hyperacetylating agent sodium butyrate abolished the suppressive effect of aPC on p66(Shc) expression both in vitro and in vivo. Moreover, sodium butyrate abolished the beneficial effects of aPC in experimental diabetic nephropathy. Inhibition of p66(Shc) expression and mitochondrial translocation by aPC normalized mitochondrial ROS production and the mitochondrial membrane potential in glucose-treated podocytes. Genetic ablation of p66(Shc) compensated for the loss of protein C activation in vivo, normalizing markers of diabetic nephropathy and oxidative stress. These studies identify a unique mechanism underlying the cytoprotective effect of aPC. Activated PC epigenetically controls expression of the redox-regulating protein p66(Shc), thus linking the extracellular protease aPC to mitochondrial function in diabetic nephropathy.

Development and validation of the Italian version of the Mobile Application Rating Scale and its generalisability to apps targeting primary prevention.

BACKGROUND: A growing body of literature affirms the usefulness of mobile technologies, including mobile applications (apps), in the primary prevention field. The quality of health apps, which today number in the thousands, is a crucial parameter, as it may affect health-related decision-making and outcomes among app end-users. The mobile application rating scale (MARS) has recently been developed to evaluate the quality of such apps, and has shown good psychometric properties. Since there is no standardised tool for assessing the apps available in Italian app stores, the present study developed and validated an Italian version of MARS in apps targeting primary prevention. METHODS: The original 23-item version of the MARS assesses mobile app quality in four objective quality dimensions (engagement, functionality, aesthetics, information) and one subjective dimension. Validation of this tool involved several steps; the universalist approach to achieving equivalence was adopted. Following two backward translations, a reconciled Italian version of MARS was produced and compared with the original scale. On the basis of sample size estimation, 48 apps from three major app stores were downloaded; the first 5 were used for piloting, while the remaining 43 were used in the main study in order to assess the psychometric properties of the scale. The apps were assessed by two raters, each working independently. The psychometric properties of the final version of the scale was assessed including the inter-rater reliability, internal consistency, convergent, divergent and concurrent validities. RESULTS: The intralingual equivalence of the Italian version of the MARS was confirmed by the authors of the original scale. A total of 43 apps targeting primary prevention were tested. The MARS displayed acceptable psychometric properties. The MARS total score showed an excellent level of both inter-rater agreement (intra-class correlation coefficient of .96) and internal consistency (Cronbach's α of .90 and .91 for the two raters, respectively). Other types of validity, including convergent, divergent, discriminative, known-groups and scalability, were also established. CONCLUSIONS: The Italian version of MARS is a valid and reliable tool for assessing the health-related primary prevention apps available in Italian app stores.

Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.

Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.

Fine-grained food image classification and recipe extraction using a customized deep neural network and NLP.

Global eating habits cause health issues leading people to mindful eating. This has directed attention to applying deep learning to food-related data. The proposed work develops a new framework integrating neural network and natural language processing for classification of food images and automated recipe extraction. It address the challenges of intra-class variability and inter-class similarity in food images that have received shallow attention in the literature. Firstly, a customized lightweight deep convolution neural network model, MResNet-50 for classifying food images is proposed. Secondly, automated ingredient processing and recipe extraction is done using natural language processing algorithms: Word2Vec and Transformers in conjunction. Thirdly, a representational semi-structured domain ontology is built to store the relationship between cuisine, food item, and ingredients. The accuracy of the proposed framework on the Food-101 and UECFOOD256 datasets is increased by 2.4% and 7.5%, respectively, outperforming existing models in literature such as DeepFood, CNN-Food, Wiser, and other pre-trained neural networks.

Greek validation of the user version of the Mobile Application Rating Scale (uMARS).

OBJECTIVE: The original user version of the Mobile Application Rating Scale (uMARS) is an English-language questionnaire that was designed to allow non-expert app users to assess the quality of health apps. We aimed to translate into the Greek language and validate the uMARS. METHODS: This was a qualitative prospective study. The World Health Organization translation process was followed and a readily available and free-of-charge app was used for the validation process. Internal consistency and reliability were tested twice within one month by 91 Greek medical students. RESULTS: The total uMARS score showed excellent internal consistency (Cronbach's alpha = 0.86). The internal consistencies of its subscales were also very high (engagement alpha = 0.71; functionality alpha = 0.71; aesthetics alpha = 0.67; information alpha = 0.63), with the notable exception of the satisfaction alpha, which was 0.61. The uMARS total score demonstrated almost perfect agreement levels in most of the subscales according to the rWG index from baseline to 1 month. CONCLUSIONS: The Greek uMARS is a reliable and valid tool for assessing the quality of mobile apps.

Development and validation of the Turkish version of the Mobile App Rating Scale - MARS-TR.

BACKGROUND: The number of mobile health apps (MHAs) is growing rapidly. MHAs have great potential to improve health and health care. However, the quality of available MHAs remains unknown due to the lack of quality assessment regulations and standards for MHAs. The Mobile Application Rating Scale (MARS) is the most widely used instrument to assess the quality of MHAs, and available in English, Italian, Spanish, German, French, Arabic and Japanese. However, the scale is currently not available in the Turkish language. OBJECTIVE: This study aimed to cross-culturally adapt the MARS into Turkish and evaluate the validity and reliability of the scale. METHODS: The MARS was translated and adapted into Turkish according to the international guidelines. A total of 52 pregnancy tracking apps were evaluated by two independent raters. Internal consistency (Cronbach's alpha), inter-rater reliability (Intraclass Correlation Coefficient [ICC]), convergent validity and concurrent validity were explored. Regarding convergent validity, MARS-TR scores were compared with the ENLIGHT scale. RESULTS: The MARS-TR was highly aligned with the original MARS. The MARS-TR showed excellent internal consistency (Cronbach's alpha of 0.95 for both raters) and excellent inter-rater reliability (ICC = 0.94; SEM = 0.02), with a smallest detectable change (95 % confidence level) of 0.05 points for the total score. Cronbach's alphas for the subscales ranged from 0.76 to 0.94 for the two raters. Correlations between the MARS-TR and ENLIGHT demonstrated adequate convergent validity (P < 0.05). No ceiling or floor effects were observed. CONCLUSION: The results provide evidence that the Turkish version of MARS is a valid and reliable tool for researchers and experts to assess the quality of MHAs in Turkey.

Validation of a Korean version of mobile app rating scale (MARS) for apps targeting disease management.

The mobile app rating scale (MARS) is a widely used instrument for evaluating smartphone app quality. We aimed to examine the reliability and validity of the Korean version of MARS (MARS-K). Two independent raters performed the assessment using the translated 23-item questionnaire. We applied intraclass correlation coefficient analysis (ICC) to examine inter-rater reliability, Omega, and item-total correlation for internal consistency, and Pearson's r for test-retest reliability and correlation between subscales and the total score of MARS-K. Most items showed moderate to good ICC (0.447-1.000). The MARS-K showed excellent internal consistency and all subscales exceeded the acceptable level of omega. Results indicated MARS-K to be a valid and reliable instrument for evaluating disease management apps offered in the Korean app store. However, upgrades are recommended to further improve MARS-K's rating accuracy and reliability.

The Persian Version of the Mobile Application Rating Scale (MARS-Fa): Translation and Validation Study.

BACKGROUND: Approximately 110 million Farsi speakers worldwide have access to a growing mobile app market. Despite restrictions and international sanctions, Iran's internal mobile health app market is growing, especially for Android-based apps. However, there is a need for guidelines for developing health apps that meet international quality standards. There are also no tools in Farsi that assess health app quality. Developers and researchers who operate in Farsi could benefit from such quality assessment tools to improve their outputs. OBJECTIVE: This study aims to translate and culturally adapt the Mobile Application Rating Scale in Farsi (MARS-Fa). This study also evaluates the validity and reliability of the newly developed MARS-Fa tool. METHODS: We used a well-established method to translate and back translate the MARS-Fa tool with a group of Iranian and international experts in Health Information Technology and Psychology. The final translated version of the tool was tested on a sample of 92 apps addressing smartphone addiction. Two trained reviewers completed an independent assessment of each app in Farsi and English. We reported reliability and construct validity estimates for the objective scales (engagement, functionality, aesthetics, and information quality). Reliability was based on the evaluation of intraclass correlation coefficients, Cronbach α and Spearman-Brown split-half reliability indicators (for internal consistency), as well as Pearson correlations for test-retest reliability. Construct validity included convergent and discriminant validity (through item-total correlations within the objective scales) and concurrent validity using Pearson correlations between the objective and subjective scores. RESULTS: After completing the translation and cultural adaptation, the MARS-Fa tool was used to assess the selected apps for smartphone addiction. The MARS-Fa total scale showed good interrater reliability (intraclass correlation coefficient=0.83, 95% CI 0.74-0.89) and good internal consistency (Cronbach α=.84); Spearman-Brown split-half reliability for both raters was 0.79 to 0.93. The instrument showed excellent test-retest reliability (r=0.94). The correlations among the MARS-Fa subdomains and the total score were all significant and above r=0.40, suggesting good convergent and discriminant validity. The MARS-Fa was positively and significantly correlated with subjective quality (r=0.90, P<.001), and so were the objective subdomains of engagement (r=0.85, P<.001), information quality (r=0.80, P<.001), aesthetics (r=0.79, P<.001), and functionality (r=0.57, P<.001), indicating concurrent validity. CONCLUSIONS: The MARS-Fa is a reliable and valid instrument to assess mobile health apps. This instrument could be adopted by Farsi-speaking researchers and developers who want to evaluate the quality of mobile apps. While we tested the tool with a sample of apps addressing smartphone addiction, the MARS-Fa could assess other domains or issues since the Mobile App Rating Scale has been used to rate apps in different contexts and languages.

Turkish Validation of the User Version of the Mobile Application Rating Scale.

OBJECTIVE: As the number of mobile health applications increases, quality assessment becomes a capital feature of any mobile application design. Besides the professional evaluation conducted before marketing the app, the perceptions of the subjects to whom is intended will determine the successful widespread dis- semination. Hence, the implementation of a given app may be impaired by the lack of a validated transla- tion and cross-cultural adaptation. We aimed to validate in the Turkish language the User Version of the Mobile Application Rating Scale, an English original scale designed to assess the quality of mobile health applications. MATERIALS AND METHODS: A well-established and predefined process of cross-cultural adaptation and transla- tion to Turkish of the User Version of the Mobile Application Rating Scale according to the World Health Organization guidelines was performed using a common, readily available, free-of-charge application. Internal consistency and reliability were tested in a population sample by Cronbach's α and rWG index, respectively. RESULTS: The total User Version of the Mobile Application Rating Scale score had good internal consistency (Cronbach's α = 0.87). Internal consistencies of its subscales were also acceptable: with Cronbach's α of 0.71, 0.78, 0.71, and 0.73 for engagement, functionality, aesthetics, and information, respectively. Cronbach's α of the satisfaction subscale was 0.46. The User Version of the Mobile Application Rating Scale total and sub- scales scores had a strong within-group agreement, all of them with rwg indexes between 0.78 and 0.87 over baseline to 1 month. CONCLUSION: The Turkish version of the User Version of the Mobile Application Rating Scale is consistent with the English original version and is a reliable and valid tool to assess the quality of mobile applications by Turkish users.

Japanese Version of the Mobile App Rating Scale (MARS): Development and Validation.

BACKGROUND: The number of mobile health (mHealth) apps continues to rise each year. Widespread use of the Mobile App Rating Scale (MARS) has allowed objective and multidimensional evaluation of the quality of these apps. However, no Japanese version of MARS has been made available to date. OBJECTIVE: The purposes of this study were (1) to develop a Japanese version of MARS and (2) to assess the translated version's reliability and validity in evaluating mHealth apps. METHODS: To develop the Japanese version of MARS, cross-cultural adaptation was used using a universalist approach. A total of 50 mental health apps were evaluated by 2 independent raters. Internal consistency and interrater reliability were then calculated. Convergent and divergent validity were assessed using multitrait scaling analysis and concurrent validity. RESULTS: After cross-cultural adaptation, all 23 items from the original MARS were included in the Japanese version. Following translation, back-translation, and review by the author of the original MARS, a Japanese version of MARS was finalized. Internal consistency was acceptable by all subscales of objective and subjective quality (Cronbach α=.78-.89). Interrater reliability was deemed acceptable, with the intraclass correlation coefficient (ICC) ranging from 0.61 to 0.79 for all subscales, except for "functionality," which had an ICC of 0.40. Convergent/divergent validity and concurrent validity were also considered acceptable. The rate of missing responses was high in several items in the "information" subscale. CONCLUSIONS: A Japanese version of MARS was developed and shown to be reliable and valid to a degree that was comparable to the original MARS. This Japanese version of MARS can be used as a standard to evaluate the quality and credibility of mHealth apps.

Metabolic Profiles, Genetic Diversity, and Genome Size of Bulgarian Population of Alkanna tinctoria.

Alkanna tinctoria (L.) Tausch Boraginaceae is a medicinal plant whose root is used for its antimicrobial and anti-inflammatory properties. A. tinctoria roots have been subject to numerous studies. However, the aerial parts have been explored less. The objective of the present study was to compare the chemical profile of aerial parts and roots as well as the total alkannin content in roots of 11 populations of the species from different floristic regions of Bulgaria. Methanolic extracts from 22 samples were analyzed by GC/MS. Phenolic, fatty, and organic acids, sterols, polyols, fatty alcohols, and sugars were identified. Ononitol (4-O-methyl-myo-inositol) was found as the main compound in the aerial parts. The total alkannin content in the roots was evaluated by the spectrophotometric method and compared with that of the commercial product. Populations with high alkannin content and rich in other bioactive compounds were identified. A relatively low genetic diversity in the studied populations was observed. The present study is the first comprehensive study on metabolite profiles and genetic diversity of the Bulgarian populations of A. tinctoria. The occurrence of ononitol in the aerial parts of the species is reported for the first time, as well as the phenolic acid profiles of the species in both aerial parts and roots. The results showed that aerial parts of the plant are also promising for use as a source of valuable biologically active substances.

Development and validation of the Japanese version of the uMARS (user version of the mobile app rating system).

BACKGROUND: Although the global market of Mobile Health Apps (mHealth apps) continues to grow dramatically, most mHealth apps still not only lack evidence base but have even not been evaluated for the basic usability or functionality. The User Version of the Mobile App Rating Scale (uMARS) was developed to allow end users to assess mHealth apps objectively and subjectively. However, there is no Japanese version of uMARS to date. OBJECTIVE: The purpose of this study is (1) to develop a validated Japanese version of uMARS and (2) to assess the translated version's reliability and validity in evaluating mHealth apps. METHODS: The original uMARS was adapted for Japanese use by four specialists using universalist cross-cultural methods. Translation/back-translation was reviewed by the author of the original version of uMARS, and confirmed. Its reliability and validity were further evaluated as part of a prospective cohort study of postoperative patients using a new mHealth app. RESULTS: Conceptual equivalence was analyzed and all items in all subcategories of the original uMARS were included in the Japanese version. Internal consistency was deemed acceptable for all subscales of objective and subjective quality with a Cronbach's alpha of 0.75-0.85. Test-retest reliability of all subscales was also acceptable with intraclass correlation coefficients (ICCs) of 0.57-0.88. Convergent/divergent validity and concurrent validity were also considered acceptable. CONCLUSION: A Japanese version of uMARS was cross-culturally validated and found to be as reliable as the original uMARS. This Japanese version of uMARS is expected to become a standard tool in assessing the quality of mHealth apps in Japan.

Pan-European phylogeography of the European roe deer (Capreolus capreolus).

To provide the most comprehensive picture of species phylogeny and phylogeography of European roe deer (Capreolus capreolus), we analyzed mtDNA control region (610 bp) of 1469 samples of roe deer from Central and Eastern Europe and included into the analyses additional 1541 mtDNA sequences from GenBank from other regions of the continent. We detected two mtDNA lineages of the species: European and Siberian (an introgression of C. pygargus mtDNA into C. capreolus). The Siberian lineage was most frequent in the eastern part of the continent and declined toward Central Europe. The European lineage contained three clades (Central, Eastern, and Western) composed of several haplogroups, many of which were separated in space. The Western clade appeared to have a discontinuous range from Portugal to Russia. Most of the haplogroups in the Central and the Eastern clades were under expansion during the Weichselian glacial period before the Last Glacial Maximum (LGM), while the expansion time of the Western clade overlapped with the Eemian interglacial. The high genetic diversity of extant roe deer is the result of their survival during the LGM probably in a large, contiguous range spanning from the Iberian Peninsula to the Caucasus Mts and in two northern refugia.