Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons.

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation, and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, which we further characterized by single nucleus RNA sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.

Effects of repeated developmental GLP-1R agonist exposure on adult behavior and hippocampal structure in mice.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are common type 2 diabetes medications that have been repurposed for adult chronic weight management. Clinical trials suggest this class may also be beneficial for obesity in pediatric populations. Since several GLP-1R agonists cross the blood-brain barrier, it is important to understand how postnatal developmental exposure to GLP-1R agonists might affect brain structure and function in adulthood. Toward that end, we systemically treated male and female C57BL/6 mice with the GLP-1R agonist exendin-4 (0.5 mg/kg, twice daily) or saline from postnatal day 14 to 21, then allowed uninterrupted development to adulthood. Beginning at 7 weeks of age, we performed open field and marble burying tests to assess motor behavior and the spontaneous location recognition (SLR) task to assess hippocampal-dependent pattern separation and memory. Mice were sacrificed, and we counted ventral hippocampal mossy cells, as we have recently shown that most murine hippocampal neuronal GLP-1R is expressed in this cell population. We found that GLP-1R agonist treatment did not alter P14-P21 weight gain, but modestly reduced adult open field distance traveled and marble burying. Despite these motor changes, there was no effect on SLR memory performance or time spent investigating objects. Finally, we did not detect any changes in ventral mossy cell number using two different markers. These data suggest developmental exposure to GLP-1R agonists might have specific rather than global effects on behavior later in life and that extensive additional study is necessary to clarify how drug timing and dose affect distinct constellations of behavior in adulthood.

Effects of repeated developmental GLP-1R agonist exposure on young adult behavior and hippocampal structure in mice.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are common type 2 diabetes medications that have been repurposed for adult chronic weight management. Clinical trials suggest this class may also be beneficial for obesity in pediatric populations. Since several GLP-1R agonists cross the blood-brain barrier, it is important to understand how postnatal developmental exposure to GLP-1R agonists might affect brain structure and function later in life. Toward that end, we systemically treated male and female C57BL/6 mice with the GLP-1R agonist exendin-4 (0.5 mg/kg, twice daily) or saline from postnatal day 14 to 21, then allowed uninterrupted development to young adulthood. Beginning at 7 weeks of age, we performed open field and marble burying tests to assess motor behavior and the spontaneous location recognition (SLR) task to assess hippocampal-dependent pattern separation and memory. Mice were sacrificed, and we counted ventral hippocampal mossy cells, as we have recently shown that most murine hippocampal neuronal GLP-1R is expressed in this cell population. We found that GLP-1R agonist treatment did not alter P14-P21 weight gain, but modestly reduced young adult open field distance traveled and marble burying. Despite these motor changes, there was no effect on SLR memory performance or time spent investigating objects. Finally, we did not detect any changes in ventral mossy cell number using two different markers. These data suggest developmental exposure to GLP-1R agonists might have specific rather than global effects on behavior later in life and that extensive additional study is necessary to clarify how drug timing and dose affect distinct constellations of behavior in young adulthood.

Exploring how informed mental health app selection may impact user engagement and satisfaction.

The prevalence of mental health app use by people suffering from mental health disorders is rapidly growing. The integration of mental health apps shows promise in increasing the accessibility and quality of treatment. However, a lack of continued engagement is one of the significant challenges of such implementation. In response, the M-health Index and Navigation Database (MIND)- derived from the American Psychiatric Association's app evaluation framework- was created to support patient autonomy and enhance engagement. This study aimed to identify factors influencing engagement with mental health apps and explore how MIND may affect user engagement around selected apps. We conducted a longitudinal online survey over six weeks after participants were instructed to find mental health apps using MIND. The survey included demographic information, technology usage, access to healthcare, app selection information, System Usability Scale, the Digital Working Alliance Inventory, and the General Self-Efficacy Scale questions. Quantitative analysis was performed to analyze the data. A total of 321 surveys were completed (178 at the initial, 90 at the 2-week mark, and 53 at the 6-week mark). The most influential factors when choosing mental health apps included cost (76%), condition supported by the app (59%), and app features offered (51%), while privacy and clinical foundation to support app claims were among the least selected filters. The top ten apps selected by participants were analyzed for engagement. Rates of engagement among the top-ten apps decreased by 43% from the initial to week two and 22% from week two to week six on average. In the context of overall low engagement with mental health apps, implementation of mental health app databases like MIND can play an essential role in maintaining higher engagement and satisfaction. Together, this study offers early data on how educational approaches like MIND may help bolster mental health apps engagement.

Passive Sensing in the Prediction of Suicidal Thoughts and Behaviors: Protocol for a Systematic Review.

BACKGROUND: Suicide is a severe public health problem, resulting in a high number of attempts and deaths each year. Early detection of suicidal thoughts and behaviors (STBs) is key to preventing attempts. We discuss passive sensing of digital and behavioral markers to enhance the detection and prediction of STBs. OBJECTIVE: The paper presents the protocol for a systematic review that aims to summarize existing research on passive sensing of STBs and evaluate whether the STB prediction can be improved using passive sensing compared to prior prediction models. METHODS: A systematic search will be conducted in the scientific databases MEDLINE, PubMed, Embase, PsycINFO, and Web of Science. Eligible studies need to investigate any passive sensor data from smartphones or wearables to predict STBs. The predictive value of passive sensing will be the primary outcome. The practical implications and feasibility of the studies will be considered as secondary outcomes. Study quality will be assessed using the Prediction Model Risk of Bias Assessment Tool (PROBAST). If studies are sufficiently homogenous, we will conduct a meta-analysis of the predictive value of passive sensing on STBs. RESULTS: The review process started in July 2022 with data extraction in September 2022. Results are expected in December 2022. CONCLUSIONS: Despite intensive research efforts, the ability to predict STBs is little better than chance. This systematic review will contribute to our understanding of the potential of passive sensing to improve STB prediction. Future research will be stimulated since gaps in the current literature will be identified and promising next steps toward clinical implementation will be outlined. TRIAL REGISTRATION: OSF Registries osf-registrations-hzxua-v1; https://osf.io/hzxua. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42146.

Accessibility and availability of smartphone apps for schizophrenia.

App-based interventions have the potential to enhance access to and quality of care for patients with schizophrenia. However, less is known about the current state of schizophrenia apps in research and how those translate to publicly available apps. This study, therefore, aimed to review schizophrenia apps offered on marketplaces and research literature with a focus on accessibility and availability. A search of recent reviews, gray literature, PubMed, and Google Scholar was conducted in August 2022. A search of the U.S. Apple App Store and Google Play App Store was conducted in July 2022. All eligible studies and apps were systematically screened/reviewed. The academic research search produced 264 results; 60 eligible studies were identified. 51.7% of research apps were built on psychosis-specific platforms and 48.3% of research apps were built on non-specific platforms. 83.3% of research apps offered monitoring functionalities. Only nine apps, two designed on psychosis-specific platforms and seven on non-specific platforms were easily accessible. The search of app marketplaces uncovered 537 apps; only six eligible marketplace apps were identified. 83.3% of marketplace apps only offered psychoeducation. All marketplace apps lacked frequent updates with the average time since last update 1121 days. There are few clinically relevant apps accessible to patients on the commercial marketplaces. While research efforts are expanding, many research apps are unavailable today. Better translation of apps from research to the marketplace and a focus on sustainable interventions are important targets for the field.

Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis.

Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through expression of its receptor, GLP-1R. RNA-seq demonstrated that most, though not all, Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 µg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study adds to known MC activity modulators a neurohormonal mechanism that may preferentially affect ventral DG physiology and may potentially be targetable by several GLP-1R pharmacotherapies already in clinical use.

Bilateral paranasal sinus fungal balls: A retrospective cohort study in 28 patients over a 21-year period.

Paranasal fungal balls are rare entities for which a recent increase in reported cases has been observed. Fungal balls are most commonly unilateral, and there are few bilateral cases in the literature. Here we report the clinical features of bilateral fungal balls in 24 patients treated in our institution over the past 20 years. In this retrospective study, we reviewed the medical records of 5279 patients who underwent endoscopic sinus surgery performed by a single surgeon from January 1996 to December 2016 at a tertiary care center in order to identify patients diagnosed with fungal balls confirmed histopathologically. Demographic data and radiologic findings of patients with bilateral fungal balls were compared with those who had unilateral fungal balls. Multiple logistic regression test was used to compare demographic information between patients with unilateral and bilateral fungal balls. The most commonly involved sinus in bilateral cases was maxillary (87.5%), followed by ethmoid (37.5%) and sphenoid (33.3%). Of the 24 patients, 19 were female, and patient age ranged from 45 to 83 years, with an average of 65.1 years. Common existing comorbidities were hypertension (45.8%), diabetes (29.2%), cardiac problem (16.7%), cerebral infarction (8.3%), pulmonary tuberculosis (8.3%), and lung cancer (4.2%). The clinically relevant features of patients diagnosed with bilateral fungal balls from our review include advanced age and immunocompromised status compared to those with unilateral fungal balls. These features contribute to the clinical distinction of bilateral fungal ball disease from unilateral fungal balls and invasive fungal sinusitis.

Antimicrobial Activity and Action Mechanisms of Arg-Rich Short Analog Peptides Designed from the C-Terminal Loop Region of American Oyster Defensin (AOD).

American oyster defensin (AOD) was previously purified from acidified gill extract of the American oyster, Crassostrea virginica. AOD is composed of 38 amino acids with three disulfide bonds and exhibits strong antimicrobial activity against Gram-positive bacteria as well as significant activity against Gram-negative bacteria. Here, to develop promising peptides into antibiotic candidates, we designed five arginine-rich analogs (A0, A1, A2, A3, and A4), predicted their loop and extended strand/random structures-including nine amino acids and a disulfide bond derived from the C-terminus of AOD-and described their antimicrobial and cytotoxic effects, as well as their modes of action. In our experimental results, the A3 and A4 analogs exhibited potent antimicrobial activity against all test organisms-including four Gram-positive bacteria, six Gram-negative bacteria, and Candida albicans-without cell toxicity. A sequence of experiments, including a membrane permeabilization assay, DNA binding study, and DNA polymerization inhibition test, indicated that the two analogs (A3 and A4) possibly did not act directly on the bacterial membrane but instead interacted with intracellular components such as DNA or DNA amplification reactions. AOD analogs also showed strong bacterial inhibition activity in the plasma environment. In addition, analog-treated microbial cells clearly exhibited membrane disruption, damage, and leakage of cytoplasmic contents. Collectively, our results suggest that two analogs, A3 and A4, have potent antimicrobial activity via DNA interaction and have the potential for development into novel antimicrobial agents.

Male-Specific and Somatic Coliphage Profiles from Major Aquaculture Areas in Republic of Korea.

Human and animal feces are important sources of various types of microbial contamination in water. Especially, enteric viruses, the major agents of waterborne infection, can attain long-term survival in water environments due to their strong resistance to various environmental factors including pH, salinity, and temperature. Coliphages are promising viral indicators for fecal contamination in water environments. Here, we investigated the seasonal and spatial distribution of male-specific and somatic coliphages in surface water and seawater at three major aquaculture areas, including Goseong Bay, Aphae Island, and Gomso Bay, in Republic of Korea over a period of 1 year. We selected 6 surface water and 14 seawater sampling sites for each study area and collected a total of 480 water samples from March 2014 to February 2015. Overall, surface water samples contained higher occurrences of coliphages than seawater samples. The high coliphage concentrations were detected in spring (March to May 2014). The differences in geographical features and patterns in land usage of the three aquaculture areas may have affected the coliphage concentration and occurrence. Moreover, environmental factors such as cumulative precipitation were strongly correlated with coliphage concentrations. Therefore, we suggest that further longitudinal studies on coliphage concentrations and distributions should be performed to support the application of coliphages in tracking fecal contamination in water.

Long-Term Clinical Effects of Carotid Intraplaque Neovascularization in Patients with Coronary Artery Disease.

OBJECTIVE: To investigate the predictive value of intraplaque neovascularization (IPN) for cardiovascular outcomes. MATERIALS AND METHODS: We evaluated 217 patients with coronary artery disease (CAD) (158 men; mean age, 68 ± 10 years) with a maximal carotid plaque thickness ≥ 1.5 mm for the presence of IPN using contrast-enhanced ultrasonography. We compared patients with (n = 116) and without (n = 101) IPN during the follow-up period and investigated the predictors of major adverse cardiovascular events (MACE), including cardiac death, myocardial infarction, coronary artery revascularization, and transient ischemic accident/stroke. RESULTS: During the mean follow-up period of 995 ± 610 days, the MACE rate was 6% (13/217). Patients with IPN had a higher maximal thickness than those without IPN (2.86 ± 1.01 vs. 2.61 ± 0.84 mm, p = 0.046). Common carotid artery-peak systolic velocity, left ventricular mass index (LVMI), and ventricular-vascular coupling index were significantly correlated with MACE. However, on multivariate Cox regression analysis, increased LVMI was independently related to MACE (p < 0.05). The presence of IPN could not predict MACE. CONCLUSION: The presence of IPN was related to a higher plaque thickness but could not predict cardiovascular outcomes better than conventional clinical factors in patients with CAD.

Is septal deviation associated with headache?: A nationwide 10-year follow-up cohort study.

To investigate the potential relationship between septal deviation (SD) and headache using nationwide representative cohort sample data.This study used a nationwide cohort sample from the Korean National Health Insurance Service database. The cohort sample was composed of 1 million patients, which is obtained by propensity score matching from 2002 to 2013. There were 9171 individuals in the SD group and 28243 in the control or no SD group. The Kaplan-Meier survival analysis, the log-rank test, and Cox proportional hazard regression analysis were used to calculate the incidence, survival curve, and hazard ratio of headache for each group.There were no statistically significant differences in sex (P = .7708), age (P = .991), residential area (P = .9626), or socioeconomic status (P = .9982) between the 2 groups. The survival curve between SD and control or no SD showed a statistically significant difference. The adjusted hazard ratio for headache incidence during the 10-year follow-up period of the SD group was 1.37 (95% CI: 1.31-1.43).This cohort study suggests that SD is associated with headache. Therefore, these findings suggest that septoplasty can be considered as 1 of the treatment option in SD patients with headache.

Roles of PI3K pan-inhibitors and PI3K-δ inhibitors in allergic lung inflammation: a systematic review and meta-analysis.

Meta-analysis can be applied to study the effectiveness of the summary estimates for experimental papers, producing objective and unbiased results. We investigated the effects of phosphoinositide-3-kinase (PI3K) on the inflammatory profile in allergic mouse models, which are currently under development in signal transduction materials. PubMed, EMBASE and Web of Science databases were searched for relevant literature using the search terms " PI3K inhibitor" and "allergy" or "asthma". Cochrane Review Manager and R were used for handling continuous variables. The primary outcomes of the inflammatory profile were divided into cell counts and inflammatory cytokines. We used a random effects model to draw a forest plot. Through the database search and subsequent selection, 17 articles were identified. Regarding the cell counts, both the PI3K pan-inhibitors and PI3K-δ inhibitors effectively reduced the total cell counts, eosinophils, neutrophils and lymphocytes. In contrast to PI3K-δ inhibitors, PI3K pan-inhibitors effectively reduced macrophages. Regarding the inflammatory cytokines, PI3K pan-inhibitors and PI3K-δ inhibitors effectively reduced total IgE, IL-4, IL-5, IL-13, TNF-α, IL-1ß, VEGF and had no effect on IL-6. Compared to the PI3K pan-inhibitors, which block all pathways, selective PI3K-δ inhibitors are expected to be relatively less toxic. Regarding the efficacy, PI3K-δ inhibitors have at least the same or better efficacy than PI3K pan-inhibitors in effector cells and inflammatory mediators.

Reduced Coronary Flow Reserve Is Associated with Impaired Ventricular-vascular Interaction in Patients with Obstructive Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (OSA) is associated with cardiac and arterial damage and adverse cardiovascular outcomes. We aimed to determine whether coronary flow reserve (CFR), which represents microvascular dysfunction, might be associated with the ventricular-vascular coupling index (VVI), which represents the afterload-adjusted contractility in patients with OSA. Methods: We enrolled 281 patients (257 males; mean age, 43±11 years) with newly diagnosed OSA. Transthoracic echocardiography was performed, and adenosine-associated CFR was measured in the left anterior descending coronary artery. We evaluated the differences between the patients with normal CFR ≥2.5 and reduced CFR <2.5. VVI was calculated using the effective arterial elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees) as follows: 10×Ea/Ees. Results: The normal CFR group (n=214) showed increased Ees (7.28±2.31 vs. 8.14±2.33 mmHg/mL, p=0.016) and preserved VVI (3.17±1.53 vs. 2.78±1.20, p=0.044) compared with the reduced CFR group (n=67). There were no differences in LV dimension, LV ejection fraction, left atrial-volume index, E/e', left atrial strain and LV global longitudinal strain between the 2 groups (all p>0.05). CFR was significantly correlated to Ees (r=0.139; p=0.023) and VVI (r=-0.137; p=0.025). Conclusions: Reduced CFR is associated with decreased Ees and impaired VVI in OSA patients. It suggests the necessity of more intensive observation in OSA patients with reduced CFR to improve cardiovascular outcomes.

Efficacy and safety of gemigliptin as add-on therapy to insulin, with or without metformin, in patients with type 2 diabetes mellitus (ZEUS II study).

The objective of this study was to evaluate the efficacy and safety of gemigliptin added to a stable dose of insulin alone or of insulin in combination with metformin in patients with type 2 diabetes mellitus. After a two-week run-in period, patients were randomized 2:1 to receive gemigliptin 50 mg or placebo once daily as add-on to background therapy with insulin or insulin plus metformin for 24 weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) from baseline at Week 24. Baseline characteristics were similar between the gemigliptin (n = 188) and placebo (n = 95) groups in terms of HbA1c (8.1%). At Week 24, the gemigliptin group showed a statistically significant reduction in mean HbA1c from baseline as compared with placebo (between-group mean difference, -0.7% [95% CI, -0.9% to -0.4%]; P-value < 0.0001). The incidence of overall adverse events and the number of hypoglycaemic adverse events were similar between the study groups. Gemigliptin added to insulin alone or to insulin in combination with metformin resulted in superior glycaemic control compared to that in the placebo group and was well tolerated for 24 weeks in patients with type 2 diabetes mellitus, without causing weight gain or increasing the incidence of hypoglycaemia.

Long-Term Clinical Effects of Carotid Intraplaque Neovascularization in Patients with Coronary Artery Disease

Objective@#To investigate the predictive value of intraplaque neovascularization (IPN) for cardiovascular outcomes. @*Materials and Methods@#We evaluated 217 patients with coronary artery disease (CAD) (158 men; mean age, 68 ± 10 years) with a maximal carotid plaque thickness ≥ 1.5 mm for the presence of IPN using contrast-enhanced ultrasonography. We compared patients with (n = 116) and without (n = 101) IPN during the follow-up period and investigated the predictors of major adverse cardiovascular events (MACE), including cardiac death, myocardial infarction, coronary artery revascularization, and transient ischemic accident/stroke. @*Results@#During the mean follow-up period of 995 ± 610 days, the MACE rate was 6% (13/217). Patients with IPN had a higher maximal thickness than those without IPN (2.86 ± 1.01 vs. 2.61 ± 0.84 mm, p = 0.046). Common carotid artery-peak systolic velocity, left ventricular mass index (LVMI), and ventricular-vascular coupling index were significantly correlated with MACE. However, on multivariate Cox regression analysis, increased LVMI was independently related to MACE (p < 0.05). The presence of IPN could not predict MACE. @*Conclusion@#The presence of IPN was related to a higher plaque thickness but could not predict cardiovascular outcomes better than conventional clinical factors in patients with CAD.

Lipid keratopathy and septal abscess: Case report.

RATIONALE: Epistaxis is a common otorhinolaryngological emergency, but septal abscess has not been reported before as a complication of epistaxis. PATIENT CONCERNS: We report a case of a 51-year-old man complaining of nasal obstruction and facial numbness for 3 weeks. He had a history of epistaxis, and had been treated with electrocauterization of the left nasal septum at a local clinic 1 month earlier. DIAGNOSES: On nasal endoscopy, swelling of the septum was noticed; computed tomography (CT) was performed, and revealed a septal abscess. INTERVENTIONS: The patient was treated with incision and drainage under local anesthesia. A left vertical hemitransfixion incision was made and 4 mL of purulent material was drained. There was no quadrangular septal cartilage. OUTCOMES: On the 5th postoperative day, the patient complained of blurred vision in his right eye. Visual acuity of the left eye was 0.5, but acuity of the right eye was finger count at 50 cm. Examination of the right eye revealed a whitish fan-shaped corneal opacity on the medial side with neovascularization, diagnostic of lipid keratopathy. CONCLUSION: Electrocautery of epistaxis should be performed carefully during hemostasis, and there should be careful follow-up after the procedure to detect the occurrence of septal hematoma or septal abscess. These conditions should be treated as early as possible to avoid further serious complications. Since lipid keratopathy is difficult to treat once it occurs, care should be taken to avoid a septal abscess.