Large-scale prediction of adverse drug reactions-related proteins with network embedding.

MOTIVATION: Adverse drug reactions (ADRs) are a major issue in drug development and clinical pharmacology. As most ADRs are caused by unintended activity at off-targets of drugs, the identification of drug targets responsible for ADRs becomes a key process for resolving ADRs. Recently, with the increase in the number of ADR-related data sources, several computational methodologies have been proposed to analyze ADR-protein relations. However, the identification of ADR-related proteins on a large scale with high reliability remains an important challenge. RESULTS: In this article, we suggest a computational approach, Large-scale ADR-related Proteins Identification with Network Embedding (LAPINE). LAPINE combines a novel concept called single-target compound with a network embedding technique to enable large-scale prediction of ADR-related proteins for any proteins in the protein-protein interaction network. Analysis of benchmark datasets confirms the need to expand the scope of potential ADR-related proteins to be analyzed, as well as LAPINE's capability for high recovery of known ADR-related proteins. Moreover, LAPINE provides more reliable predictions for ADR-related proteins (Value-added positive predictive value = 0.12), compared to a previously proposed method (P < 0.001). Furthermore, two case studies show that most predictive proteins related to ADRs in LAPINE are supported by literature evidence. Overall, LAPINE can provide reliable insights into the relationship between ADRs and proteomes to understand the mechanism of ADRs leading to their prevention. AVAILABILITY AND IMPLEMENTATION: The source code is available at GitHub (https://github.com/rupinas/LAPINE) and Figshare (https://figshare.com/articles/software/LAPINE/21750245) to facilitate its use. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of Home-Based Transcranial Direct Current Stimulation on Cognitive Function in Patients with Mild Cognitive Impairment: A Two-Week Intervention.

PURPOSE: Repeated transcranial direct current stimulation (tDCS) is expected to have the potential to improve cognitive function in patients with mild cognitive impairment (MCI). We aimed to evaluate the efficacy and safety of at-home tDCS for elderly patients with MCI. MATERIALS AND METHODS: Patients aged 60-80 years, who maintained normal daily living but reported objective memory impairments, were enrolled. Active or sham stimulations were applied to the dorsal frontal cortex (left: anode; right: cathode) at home for 2 weeks. Changes in cognitive function were assessed using visual recognition tasks and the Mini-Mental State Exam (MMSE), and safety and efficacy were assessed using self-reports and a remote monitoring application. RESULTS: Of the 19 participants enrolled, 12 participants were included in the efficacy analysis. Response times and MMSE scores significantly improved after active stimulation compared to the sham stimulation; however, there were no significant differences in the proportion of correct responses. The mean compliance of the efficacy group was 97.5%±4.1%. Three participants experienced burns, but no permanent sequelae remained. CONCLUSION: This preliminary result suggests that home-based tDCS may be a promising treatment option for MCI patients; however, it requires more attention and technological development to address safety concerns. CLINICAL TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0002721.

Potential Imaging Biomarkers of Cognitive Frailty.

Cognitive frailty (CF) is a state of impairment in both cognitive and motor functions. The concept of CF has been developed in several ways. However, it is difficult to identify consistent neuroimaging findings according to the application of the operational definition of different frailty models within the same concept, as well as the diversity of the concept itself of CF. This study aimed to review neuroimaging studies of CF and to determine suitable imaging biomarkers of CF. White matter abnormalities (e.g., white matter hyperintensity and microbleeds) seem likely to be considered imaging biomarkers of CF. The volume of the cerebral/cerebellar cortex and that of the subcortical nuclei are also candidates of imaging biomarkers of CF. These imaging biomarkers are expected to be more useful in discriminating the need for screening CF in visitors of clinics or health examination centers than in detecting the presence of CF in community-dwelling older adults.

The Relationship between Delirium and Statin Use According to Disease Severity in Patients in the Intensive Care Unit.

Objective: The aim of this study was to investigate the association between the use of statins and the occurrence of delirium in a large cohort of patients in the intensive care unit (ICU), considering disease severity and statin properties. Methods: We obtained clinical and demographical information from 3,604 patients admitted to the ICU from January 2013 to April 2020. This included information on daily statin use and delirium state, as assessed by the Confusion Assessment Method for ICU. We used inverse probability of treatment weighting and categorized the patients into four groups based on the Acute Physiology and Chronic Health Evaluation II score (group 1: 0-10 - mild; group 2: 11-20 - mild to moderate; group 3: 21-30 - moderate to severe; group 4: > 30 - severe). We analyzed the association between the use of statin and the occurrence of delirium in each group, while taking into account the properties of statins. Results: Comparisons between statin and non-statin patient groups revealed that only in group 2, patients who were administered statin showed significantly higher occurrence of delirium (p = 0.004, odds ratio [OR] = 1.58) compared to the patients who did not receive statin. Regardless of whether statins were lipophilic (p = 0.036, OR = 1.47) or hydrophilic (p = 0.032, OR = 1.84), the occurrence of delirium was higher only in patients from group 2. Conclusion: The use of statins may be associated with the increases in the risk of delirium occurrence in patients with mild to moderate disease severity, irrespective of statin properties.

Evaluation of glymphatic system activity using diffusion tensor image analysis along the perivascular space and amyloid PET in older adults with objectively normal cognition: a preliminary study.

Objectives: Diffusion tensor image analysis along the perivascular space (DTI-ALPS) is a recently introduced method for the assessment of the glymphatic system without the need for contrast injection. The purpose of our study was to assess the glymphatic system in cognitively normal older adults with or without subjective cognitive decline (SCD) using DTI-ALPS, and correlating with amyloid PET. Design and participants: To evaluate the glymphatic system in cognitively normal older adults using DTI-ALPS, we built a prospective cohort including a total of 123 objectively cognitively normal older adults with or without SCD. The ALPS index was calculated from DTI MRI and was assessed by correlating it with standardized uptake value ratios (SUVRs) from amyloid PET and clinically relevant variables. The study subjects were also divided into amyloid "positive" and "negative" groups based on the result of amyloid PET, and the ALPS indices between those two groups were compared. Results: The ALPS index was not significantly different between the normal and SCD groups (P = 0.897). The mean ALPS index from the amyloid positive and amyloid negative group was 1.31 and 1.35, respectively, which showed no significant difference (P = 0.308). Among the SUVRs from variable cortices, that of the paracentral cortex was negatively correlated with the ALPS index (r = -0.218, P = 0.016). Multivariate linear regression revealed that older age (coefficient, -0.007) and higher SUVR from the paracentral cortex (coefficient, -0.101) were two independent variables with a significant association with a lower ALPS index (P = 0.015 and 0.045, respectively). Conclusion: DTI-ALPS may not be useful for evaluation of the glymphatic system in subjects with SCD. Older age was significantly associated with lower ALPS index. Greater amyloid deposition in the paracentral cortex was significantly associated with lower glymphatic activity in cognitively normal older adults. These results should be validated in future studies on the relationships between ALPS index and other fundamental compartments in glymphatic system, such as perivenous space and the meningeal lymphatic vessels.

Plasma amyloid-beta oligomer is related to subjective cognitive decline and brain amyloid status.

BACKGROUND: Subjective cognitive decline (SCD) is a target for Alzheimer's disease prediction. Plasma amyloid-beta oligomer (AßO), the pathogenic form of Aß in blood, has recently been proposed as a novel blood-based biomarker of AD prediction by representing brain Aß deposition. The relationship between plasma AßO, brain Aß deposition, and SCD in individuals with normal objective cognition has not been investigated. METHODS: In this cross-sectional study, we analyzed 126 participants with normal objective cognition. More SCD symptoms were expressed as higher scores of the Subjective Cognitive Decline Questionnaire (SCDQ) and Memory Age-associated Complaint Questionnaire (MACQ). The plasma AßO level of each participant was measured twice for validation and expressed as a concentration (ng/mL) and a ratio relative to the mean value of two internal standards. Brain Aß deposition was assessed by [18F] flutemetamol positron emission tomography (PET) and expressed as standard uptake value ratio (SUVR). Associations of SCDQ and MACQ with plasma AßO levels or SUVR were analyzed in multiple linear regression models. The association between plasma AßO level and flutemetamol PET positivity was assessed in logistic regression and receiver operative characteristic analyses. RESULTS: Overall, participants were 73.3 years old with female predominance (69.0%). After adjustment for confounders, high SCDQ and MACQ scores were associated with the high plasma AßO levels as both concentrations and ratios (ratios: standardized coefficient = 0.246 and p = 0.023 for SCDQ, standardized coefficient = 0.209 and p = 0.029 for MACQ; concentrations: standardized coefficient = 0.257 and p = 0.015 for SCDQ, standardized coefficient = 0.217 and p = 0.021 for MACQ). In contrast, SCDQ and MACQ were not significantly associated with SUVRs (p = 0.134 for SCDQ, p = 0.079 for MACQ). High plasma AßO levels were associated with flutemetamol PET (+) with an area under the curve of 0.694 (ratio) or 0.662 (concentration). Combined with APOE e4, plasma AßO presented area under the curves of 0.789 (ratio) and 0.783 (concentration). CONCLUSIONS: Our findings indicate that the high plasma AßO level could serve as a potential surrogate biomarker of severe SCD and the presence of brain Aß deposition in individuals with normal objective cognition.

Neutrophil-Lymphocyte Ratio as a Potential Biomarker for Delirium in the Intensive Care Unit.

Background: Recognition and early detection of delirium in the intensive care unit (ICU) is essential to improve ICU outcomes. To date, neutrophil-lymphocyte ratio (NLR), one of inflammatory markers, has been proposed as a potential biomarker for brain disorders related to neuroinflammation. This study aimed to investigate whether NLR could be utilized in early detection of delirium in the ICU. Methods: Of 10,144 patients who admitted to the ICU, 1,112 delirium patients (DE) were included in the current study. To compare among inflammatory markers, NLR, C-reactive protein (CRP), and white blood cell (WBC) counts were obtained: the mean NLR, CRP levels, and WBC counts between the initial day of ICU admission and the day of initial delirium onset within DE were examined. The inflammatory marker of 1,272 non-delirium patients (ND) were also comparatively measured as a supplement. Further comparisons included a subgroup analysis based on delirium subtypes (non-hypoactive vs. hypoactive) or admission types (elective vs. emergent). Results: The NLR and CRP levels in DE increased on the day of delirium onset compared to the initial admission day. ND also showed increased CRP levels on the sixth day (the closest day to average delirium onset day among DE) of ICU admission compared to baseline, while NLR in ND did not show significant difference over time. In further analyses, the CRP level of the non-hypoactive group was more increased than that of the hypoactive group during the delirium onset. NLR, however, was more significantly increased in patients with elective admission than in those with emergent admission. Conclusion: Elevation of NLR was more closely linked to the onset of delirium compared to other inflammatory markers, indicating that NLR may play a role in early detection of delirium.

Effect of drug compliance on health care costs in newly-diagnosed dementia: Analysis of nationwide population-based data.

BACKGROUND: The cost-effectiveness of both cholinesterase inhibitors and memantine by delaying nursing home placement has been supported by numerous studies. The importance of sustained pharmacological treatment in dementia has been relatively less recognized by public health policies compared to early diagnosis. We investigated the effect of the drug (donepezil, rivastigmine, galantamine, and memantine) compliance on the health care costs in newly-diagnosed dementia. METHODS: National Health Insurance Service (NHIS) database which covers the entire population of South Korea was used for analysis. Health care expenditure of patients newly-diagnosed with dementia in between 2012 and 2014 was investigated for 3-5 years. For drug compliance, we used Medication Possession Ratio (MPR) that indicates the percentage of time a patient has access to medication. Multivariate linear regression analysis including generalized estimated equation and gamma distribution was used for statistical analysis. RESULTS: We identified 252,594 patients who were both prescribed with cognitive enhancers and newly diagnosed with dementia. When initial MPR increased 20%, total health care costs decreased 8.4% (RR = 0.916, 95%; CI 0.914 to 0.916). Same relationship was shown with medical costs related to dementia, admission to a general hospital, and emergency room visits. When MPR increased 20% compared to the previous year, the total health care costs, admission to a general hospital, emergency room visits, and admission to a nursing hospital decreased. CONCLUSIONS: This population-based retrospective cohort study provides evidence that patients newly-diagnosed with dementia who showed higher initial drug compliance or maintained antidementia drugs (Cholinesterase inhibitors and memantine) would benefit in total health-care costs.

Effect of home-based transcranial direct current stimulation (tDCS) on cognitive function in patients with mild cognitive impairment: a study protocol for a randomized, double-blind, cross-over study.

BACKGROUND: The possible effect of transcranial direct current stimulation (tDCS) in improving cognitive function is clear from studies involving pre-dementia stage mild cognitive impairment (MCI). However, the application of tDCS in actual clinical practice entails repeated hospital visits almost every day for treatment. The objective of this study is to confirm the possibility of self-application of tDCS at home by elderly patients with declined cognitive function and the significant clinical effect of tDCS administered at home. METHODS/DESIGN: This study will be conducted in 20 elderly people aged 60 to 80 years with complaints of subjective memory impairment while maintaining general functions with limited activities of daily living. This study involves a cross-over design that will include 2-week active or sham stimulation of both dorsolateral prefrontal cortexes (left, anode; right, cathode) randomly with a 2-week wash-out phase. Changes in cognitive function will be evaluated using visual recognition tasks and neuropsychological tests. In this study, tDCS will be carried out by each patient at his/her home and its safety and suitability will be evaluated. DISCUSSION: In this study, patients will apply a portable tDCS, developed for home use, for more than 2 weeks. Such studies can contribute to the use of tDCS as a realistic therapy. In addition, the utility of home-based tDCS will be confirmed by application of tDCS at home by the elderly with declined cognitive function. Furthermore, confirmation of tDCS as a significant therapeutic method can facilitate treatment of Alzheimer's dementia at an early stage, including MCI. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0002721 . Registered on 9 March 2018.

Involvement of amygdala-prefrontal dysfunction in the influence of negative emotion on the resolution of cognitive conflict in patients with schizophrenia.

INTRODUCTION: Patients with schizophrenia often have impaired cognition and abnormal conflict control. Conflict control is influenced by the emotional values of stimuli. This study investigated the neural basis of negative emotion interference with conflict control in schizophrenia. METHODS: Seventeen patients with schizophrenia and 20 healthy controls underwent functional magnetic resonance imaging while performing the emotional Simon task, in which positive or negative emotional pictures were located in congruent or incongruent positions. Analysis was focused on identifying brain regions with the significant interaction among group, emotion, and conflict in whole brain voxel-wise analysis, and abnormality in their functional connectivity in the patient group. RESULTS: The regions showing the targeted interaction was the right amygdala, which exhibited significantly reduced activity in the negative congruent (t = -2.168, p = 0.036) and negative incongruent (t = -3.273, p = 0.002) conditions in patients versus controls. The right amygdala also showed significantly lower connectivity with the right dorsolateral prefrontal cortex in the cognitive and emotional loading contrast (negative incongruent-positive congruent) in patients versus controls (t = -5.154, p < 0.01), but not in the cognitive-only or emotional-only loading contrast. CONCLUSIONS: These results suggest that negative emotion interferes with cognitive conflict resolution in patients with schizophrenia due to amygdala-dorsolateral prefrontal cortex disconnection. Based on these findings, interventions targeting conflict control under negative emotional influence may promote cognitive rehabilitation in patients with schizophrenia.

Delirium characteristics and outcomes in medical and surgical lnpatients: A subgroup analysis.

PURPOSE: Persistent delirium can negatively affect patients, increase healthcare costs, and extend the length of hospital stays. This investigation was undertaken to explore associations between patient characteristics and delirium outcomes. MATERIALS AND METHODS: Intensive care unit (ICU) and medical and surgical ward inpatients for whom psychiatric consultation was requested for delirium were included in this study. Delirium screening and ongoing assessments were conducted using the Confusion Assessment Method for ICU patients. RESULTS: Postoperative delirium developing as a secondary complication following surgery was found to be of significantly longer duration and associated with greater length of hospitalization compared with postoperative delirium attributable to surgery and delirium in medical patients. Medical patients with delirium had lower delirium recovery rates at discharge compared with surgical patients. CONCLUSIONS: The findings that patient type and timing of postoperative delirium are associated with differential delirium outcomes suggest that targeted screening and intervention approaches may be needed. Medical patients were more likely to be discharged before recovery from delirium compared with surgical patients. Differences in underlying chronic medical conditions may account for the observed differences in discharge condition between medical and surgical patients with delirium.

Development and evaluation of a mobile-optimized daily self-rating depression screening app: A preliminary study.

The aims of this study were to design a mobile app that would record daily self-reported Korean version of the Center for Epidemiologic Studies Depression Scale-Revised (K-CESD-R) ratings in a "Yes" or "No" format, develop two different algorithms for converting mobile K-CESD-R scores in a binary format into scores in a 5-point response format, and determine which algorithm would be more appropriately applied to the newly developed app. Algorithm (A) was designed to improve the scoring system of the 2-week delayed retrospective recall-based original K-CESD-R scale, and algorithm (B) was designed to further refine the scoring of the 24-hour delayed prospective recall-based mobile K-CESD-R scale applied with algorithm (A). To calculate total mobile K-CESD-R scores, each algorithm applied certain cut-off criteria for a 5-point scale with different inter-point intervals, defined by the ratio of the total number of times that users responded "Yes" to each item to the number of days that users reported daily depressive symptom ratings during the 2-week study period. Twenty participants were asked to complete a K-CESD-R Mobile assessment daily for 2 weeks and an original K-CESD-R assessment delivered to their e-mail accounts at the end of the 2-week study period. There was a significant difference between original and mobile algorithm (B) scores but not between original and mobile algorithm (A) scores. Of the 20 participants, 4 scored at or above the cut-off criterion (≥13) on either the original K-CESD-R (n = 4) or the mobile K-CESD-R converted with algorithm (A) (n = 3) or algorithm (B) (n = 1). However, all participants were assessed as being below threshold for a diagnosis of a mental disorder during a clinician-administered diagnostic interview. Therefore, the K-CESD-R Mobile app using algorithm (B) could be a more potential candidate for a depression screening tool than the K-CESD-R Mobile app using algorithm (A).

The Effects of a Delirium Notification Program on the Clinical Outcomes of the Intensive Care Unit: A Preliminary Pilot Study.

BACKGROUND: Delirium is common among intensive care unit (ICU) patients, so recent clinical guidelines recommended routine delirium monitoring in the ICU. But, its effect on the patient's clinical outcome is still controversial. In particular, the effect of systems that inform the primary physician of the results of monitoring is largely unknown. METHODS: The delirium notification program using bedside signs and electronic chart notifications was applied to the pre-existing delirium monitoring protocol. Every patient was routinely evaluated for delirium, pain, and anxiety using validated tools. Clinical outcomes, including duration of delirium, ICU stay, and mortality were reviewed and compared for 3 months before and after the program implementation. RESULTS: There was no significant difference between the two periods of delirium, ICU stay, and mortality. However, anxiety, an important prognostic factor in the ICU survivor's mental health, was significantly reduced and pain tended to decrease. CONCLUSIONS: Increasing the physician's awareness of the patient's mental state by using a notification program could reduce the anxiety of ICU patients even though it may not reduce delirium. The results suggested that the method of delivering the results of monitoring was also an important factor in the success of the delirium monitoring program.

Prediction and early detection of delirium in the intensive care unit by using heart rate variability and machine learning.

OBJECTIVE: Delirium is an important syndrome found in patients in the intensive care unit (ICU), however, it is usually under-recognized during treatment. This study was performed to investigate whether delirious patients can be successfully distinguished from non-delirious patients by using heart rate variability (HRV) and machine learning. APPROACH: Electrocardiography data of 140 patients was acquired during daily ICU care, and HRV data were analyzed. Delirium, including its type, severity, and etiologies, was evaluated daily by trained psychiatrists. HRV data and various machine learning algorithms including linear support vector machine (SVM), SVM with radial basis function (RBF) kernels, linear extreme learning machine (ELM), ELM with RBF kernels, linear discriminant analysis, and quadratic discriminant analysis were utilized to distinguish delirium patients from non-delirium patients. MAIN RESULTS: HRV data of 4797 ECGs were included, and 39 patients had delirium at least once during their ICU stay. The maximum classification accuracy was acquired using SVM with RBF kernels. Our prediction method based on HRV with machine learning was comparable to previous delirium prediction models using massive amounts of clinical information. SIGNIFICANCE: Our results show that autonomic alterations could be a significant feature of patients with delirium in the ICU, suggesting the potential for the automatic prediction and early detection of delirium based on HRV with machine learning.

Comparative evaluation of three calcium phosphate synthetic block bone graft materials for bone regeneration in rabbit calvaria.

Various synthetic materials were developed to be used for implant dentistry and periodontal treatments. Among the various synthetic bone substitutes, calcium phosphate ceramics have been extensively investigated because their mineral chemistry resembles that of human bone. We evaluated the regeneration of three calcium phosphate synthetic block bone grafts in rabbit calvarial noncritical size defects. Four 8-mm-diameter defects were created in each rabbit (N = 10). Three defects, hydroxyapatite (HA), beta-tricalcium phosphate (ß-TCP), and biphasic calcium phosphate (BCP), were randomly filled with one of three fabricated synthetic block bone graft materials. The fourth defect was filled with blood clots. Specimens were harvested at 4 and 8 weeks postsurgery. Histological and histometrical findings indicated that all three calcium phosphate block bone graft materials were able to maintain space significantly better than the control group at both 4 and 8 weeks. In the BCP group, the amount of newly formed bone was increased more than for the other groups. Additionally, ß-TCP showed a large resorption of graft materials after 4 weeks postsurgery, while there were only small resorption for HA and BCP.