Journal of Dementia and Alzheimer's Disease

Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that disrupts functional brain connectivity, leading to cognitive and functional decline. Electroencephalography (EEG), a noninvasive and cost-effective technique, has gained attention as a promising tool for studying brain network alterations in AD. This study aims to leverage EEG-derived connectivity metrics to differentiate between healthy controls (HC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, offering insights into disease progression. Methods: Using graph theory-based analysis, we extracted key connectivity metrics from resting-state EEG signals, focusing on the betweenness centrality and clustering coefficient. Statistical analysis was conducted across multiple EEG frequency bands, and discriminant analysis was applied to evaluate the classification performance of connectivity metrics. Results: Our findings revealed a progressive increase in theta-band betweenness centrality and a concurrent decrease in alpha- and beta-band centrality, reflecting AD-related network reorganization. Among the examined metrics, theta-band betweenness centrality exhibited the highest discriminative power in distinguishing AD stages. Additionally, classification performance using connectivity metrics was comparable to advanced deep learning models, highlighting their potential as predictive biomarkers. Conclusions: EEG-derived connectivity metrics demonstrate strong potential as noninvasive biomarkers for the early detection and monitoring of AD progression. Their effectiveness in capturing network alterations underscores their value in clinical diagnostic workflows, offering a scalable and interpretable alternative to deep learning-based models for AD classification. Full article

Background/Objectives: Sex differences in the relationship between subjective cognitive decline (SCD) and health-related quality of life (HRQOL), as well as psychological and physical factors affecting this relationship, have not been fully investigated. In this study, we aimed to examine the relationship between SCD severity and HRQOL in community-dwelling older adults in Japan and to clarify the psychological and physical factors affecting this relationship by sex. Methods: This cross-sectional study included 456 community-dwelling older adults and was conducted in September 2024. SCD severity was evaluated using the visual analog scale, and HRQOL was assessed using the EuroQol 5-Dimensions 5-Levels. Psychological factors (depression and insomnia) and physical factors (pain and frailty) were measured, and the relationship between SCD and HRQOL was analyzed by sex. Results: In women, HRQOL decreased as SCD severity increased and was associated with depression, insomnia, and physical pain. Conversely, in men, the association between SCD and HRQOL was not significant, and HRQOL was mainly associated with physical health factors, including pain and frailty. Conclusions: There were sex differences in the relationship between SCD and HRQOL, with women’s awareness of SCD associated with a decline in HRQOL, whereas physical health was the main determinant in men. Sex-specific interventions with psychological support being effective for women and support focusing on maintaining physical health for men are warranted. Full article

Background/Objective: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer’s disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer’s disease. Methods: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin. Results: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin–NFAT pathway, like cyclo-sporine A, providing a potential mechanism. Conclusions: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer’s disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer’s disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration. Full article

Background: Sex differences in the association of cognitive function and imaging measures with dementia have not been fully investigated. Understanding sex differences in the dementia-related socioeconomic, cognitive, and imaging measurements is crucial for uncovering sex-related pathways to dementia and facilitating early diagnosis, family planning, and cost control. Methods: We selected data from the Open Access Series of Imaging Studies, with longitudinal measurements of brain volumes, on 150 individuals aged 60 to 96 years. Dementia status was determined using the Clinical Dementia Rating (CDR) scale, and Alzheimer’s disease was diagnosed as a CDR of ≥0.5. Generalized estimating equation models were used to estimate the associations of socioeconomic, cognitive, and imaging factors with dementia in men and women. Results: The study sample consisted of 88 women (58.7%) and 62 men (41.3%), and the average age of the subjects was 75.4 years at the initial visit. A lower socioeconomic status was associated with a reduced estimated total intracranial volume in men, but not in women. Ageing and lower MMSE scores were associated with a reduced nWBV in both men and women. Lower education affected dementia more in women than in men. Age, education, Mini-Mental State Examination (MMSE), and normalized whole-brain volume (nWBV) were associated with dementia in women, while only MMSE and nWBV were associated with dementia in men. Conclusions: The association between education and the prevalence of dementia differs in men and women. Women may have more risk factors for dementia than men. Full article

Background: Dementia patients often experience a decline in both their cognitive and sensory functions, particularly hearing, which significantly impacts their quality of life. This study evaluates the effectiveness of a combined Digital Cognitive Stimulation Therapy (DKST) and online hearing training intervention in enhancing the quality of life of individuals with dementia. Methods: Twenty-three patients participated in a six-month program integrating cognitive exercises and hearing rehabilitation, facilitated by trained co-therapists. Quality of life was assessed using the Quality of Life (QoL) Questionnaire, while the Mini-Mental State Examination (MMSE) was employed to categorize participants based on their cognitive status. Results: The results revealed significant improvements in the overall quality of life. Conclusions: This study demonstrates that combining DKST with hearing training effectively addresses sensory and cognitive challenges, supporting improved quality of life and highlighting the potential of digital interventions in dementia care. Full article

Background/Objectives: The aging population presents significant challenges to healthcare systems, with conditions like dementia severely affecting the quality of life for older adults, especially those in long-term care. Gamification has the potential to motivate older adults to engage in exercise by transforming physical activities into enjoyable experiences. Incorporating gaming elements in cycling exercises can foster a sense of interest and achievement, potentially improving health outcomes. This pilot study aims to explore interdisciplinary staff perspectives on using a digital game to motivate cycling exercise among residents living with dementia in long-term care (LTC). Methods: This study applied a qualitative description design. Using an interpretive description approach, we conducted focus groups with 29 staff members, including recreational therapists, rehabilitation therapists, nurses, care aides, and leadership in an LTC home. The consolidated framework for implementation research (CFIR) guided the data analysis to identify barriers and facilitators to adopting the digital game. Results: Engaging LTC residents living with dementia presents various challenges. Identified potential barriers to implementing the cycling game include cognitive and physical limitations, resistance to change, and intervention complexity. Frontline staff strategies include flexible invitations, social groups, making it fun, and building rapport. Success relies heavily on its cultural and individual relevance, along with strong support from leadership, peers, and family. Conclusions: This pilot study explored staff perspectives on the potential integration of a gamified cycling intervention for older adults with dementia in long-term care settings. Staff emphasized that successful implementation would depend on addressing key barriers and identifying enabling strategies. Based on these findings, practice implications were provided to support effective integration. Further research, including resident input and long-term evaluations, is needed to assess the feasibility, acceptance, and effectiveness of gamification in promoting health outcomes for this population. This study adhered to the COREQ Checklist. Full article

Aim: Our aim was to survey people with dementia and their carers with respect to their propensity to join a randomized trial of community singing in dementia, in the context of uncertainty following the COVID-19 pandemic. Method: We employed an online anonymous questionnaire, comparing activities before and after lockdown, worries about COVID-19, whether people would attend a singing group and what measures might make this more likely. With a target sample of 100, the survey was distributed to the general population of people with dementia and carers in the UK between June and August 2022. Results: We had a total of 168 respondents, of whom 30% were people living with dementia and 70% were carers. Those who were not worried (roughly 62%) were more likely to go out to groups. Worries about COVID-19 affected 38% of respondents but some judged the risk of going out to be worthwhile. Most felt able to take adequate precautions against infection. However, COVID-19 transmission was not the main impediment to attending a singing group and 19% of respondents were simply not interested in doing so, while mobility and shyness deterred others. Conclusions: Given recruitment problems, quantitative studies of singing in dementia need to take account of individual preferences as well as contextual barriers, including fear of virus transmission, individual perceptions of the intervention and logistical obstacles to participation. Full article

Introduction: Percutaneous endoscopic gastrostomy (PEG) placement does not generate consensus in palliative care, given the existing doubts about whether it significantly contributes to an improvement in patient outcomes such as survival, quality of life and symptomatic control. Objective: This study explored the impact of percutaneous endoscopic gastrostomy placement on survival and quality of life in patients under community palliative care in Northern Portugal. Methods: This observational, retrospective cohort study involved 54 patients monitored by a specialized palliative care team between March 2020 and December 2023. The key outcomes assessed included the survival rates, the main diagnoses leading to PEG requests, and the influence of PEG placement on survival and the place of death. Results: The statistical analysis revealed that the survival time was significantly longer in females compared to males (p = 0.003). The main reason for PEG requests was dysphagia, especially in patients with dementia and oncological diseases. No significant correlations were found between PEG placement and the age at death, survival time, or palliative performance scores (PPS). However, the study identified a moderate positive correlation between the follow-up time and survival after PEG placement (r = 0.457, p < 0.001) and a low rate of complications (11% of patients with minor complications and none with severe complications). Conclusions: This study emphasizes the role of timely PEG placement and social support in improving patient outcomes. Additionally, patients whose PEG was requested by the study’s palliative care team demonstrated better survival outcomes compared to those referred by other teams. The findings underscore the need for individualized decision-making in PEG placement and suggest that this procedure is safe and increases patient longevity and quality of life, avoiding the high rate of complications associated with nasogastric tubes in fragile patients in need of specialized palliative care. Full article

(1) Background: Alterations in brain functional connectivity (FC) precede clinical symptoms of Alzheimer’s disease (AD) by decades, presenting opportunities for early diagnosis. However, conventional FC analyses measure correlations between brain regions and do not provide insights into directional, causal interactions. Causal functional connectivity (CFC), which infers directed interactions between regions, addresses this limitation. This study aims to identify disrupted CFC networks in AD compared to cognitively normal (CN) individuals. (2) Methods: The recently developed Time-aware PC (TPC) algorithm was employed to infer directed CFC from functional magnetic resonance imaging (fMRI) data. These results were compared with traditional correlation-based FC obtained via sparse partial correlation. Network-based Statistics (NBS) for directed networks was used to identify altered CFC sub-networks, with corrections for multiple comparisons applied at the 5% significance level. (3) Results: Key causal networks, including the inferior frontal gyrus, superior temporal gyrus, middle temporal gyrus, and cerebellum, showed significantly reduced strength in AD compared to CN (p = 0.0299; NBS corrected). Instead of detecting disruptions at the level of individual edges, this study identifies network-level alterations, revealing systemic disruptions in brain connectivity. (4) Conclusions: This study demonstrates the utility of CFC analysis in uncovering network-level disruptions in AD. The identified disrupted networks align with published medical literature and provide a framework for future studies with larger datasets. Full article

Introduction: Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia, sleep fragmentation, daytime sleepiness, cognitive impairment, and brain cell damage due to brain blood flow reduction, with ischemic damage, increased microvascular reactivity, and brain tissue damage. OSAS is strongly linked to chronic, neurodegenerative, and inflammatory cerebrovascular disease and cognitive impairment. Continuous positive airway pressure (CPAP) is the first-line treatment for OSAS. Objective: This article aims to evaluate the effect of CPAP treatment on neurocognitive performance in OSAS patients with mild cognitive impairment or dementia by reviewing the literature. Methods: We performed a comprehensive review of the Portuguese and English languages without a time limit using the following Mesh terms: dementia, mild cognitive impairment, obstructive sleep apnea, and CPAP. We included randomized controlled trials (RCTs), meta-analyses, and systematic reviews (SRs) where the impact of CPAP on neurocognitive performance was addressed. Results: Five SRs and three RCTs reported significant improvements in neurocognitive performance, especially in verbal, visuospatial, and working memory. Conclusion: CPAP treatment seems to improve cognitive defects associated with OSA. Full article

Alzheimer’s disease (AD) is the most common cause of dementia, and no cure is currently available. The β-amyloid cascade of AD and neurofibrillary tangles are the basis of the current understanding of AD pathogenesis, driving drug investigation and other discoveries. Up until now, no AD models have entirely validated the β-amyloid cascade hypothesis. AD models must be capable of recapitulating the critical events of this pathology, including β-amyloid plaques and neurofibrillary tangles. The development of plaques is probably derived from the amyloid precursor protein (APP) and presenilin 1 (PS1) familial Alzheimer’s disease (FAD) mutations, while the tangle-like pathology is determined by tau mutations. Transgenic mouse models struggle to replicate the entire spectrum of AD, particularly neuronal death stemming from β-amyloid and tau pathologies. Furthermore, the success of these transgenic mice often relies on the overexpression of APP transgenes enclosing FAD-associated mutations at levels beyond physiological. Ultimate species-specific discrepancies in genome and protein composition between the human and the mouse may hinder the accurate recapitulation of AD pathological events in mouse models. Although none of the AD models fully mirrors human pathology, these experimental in vivo animal models have provided valuable insights into β-amyloid toxicity and the overall pathophysiological basis of AD. Therefore, these experimental models have been widely used in the preclinical evaluation of therapeutic strategies and have played a pivotal role in the development of immunotherapies for AD. In this review, we sum up the main transgenic mouse models used for AD research, whether they are APP mutation-based mice, APP plus presenilin mutation-based mice, or tau mutation-based mice. The specific characteristics of each mouse model and the significance of their use for AD research, focusing on their current advantages and disadvantages, as well as on the progress made and the forthcoming challenges in replicating this neurodegenerative disease, are also highlighted. Full article

Context: The systematic evaluation of a practitioner’s adherence to and competence in delivering psychotherapeutic interventions can be complex. This study describes the development of a fidelity assessment tool for the Reitman Centre CARERS Program (RCCP), a carer group-psychotherapy intervention with multiple didactic and clinical components. The tool’s value in informing psychotherapy training and best practices for practitioners from diverse professional settings is examined. Methods: The RCCP Fidelity Assessment Tool (RCCP-FAT) was developed following an iterative process of item writing and checking. Seven components of the RCCP—Group Structure, Dementia Education, Problem-Solving Techniques, Therapeutic Simulation, Vertical Cohesion, Horizontal Cohesion, and Overall Global Rating—were assessed, with three to eight items, and a “global score” assigned to each. Fifteen trained raters were paired up to rate 36 RCCP sessions using the RCCP-FAT. Rater agreement, correlation between itemized and global scores, and correlation between global ratings and RCCP participants’ satisfaction were calculated. Results: A total of 1188 RCCP-FAT items were rated by each of the two rater groups. Rater agreement was calculated to be 54.3% (κ = 0.32; 95% CI, 0.02681–0.3729). A positive correlation was found between the itemized and global scoring for four RCCP components evaluated (R = 0.833 to 0.929; p < 0.01). The global score and the participants’ satisfaction with “Simulation” was also positively correlated (R = 0.626, p < 0.01). Conclusions: The study provided evidence for fair rater agreement for all RCCP-FAT assessment items. More importantly, the process of developing the tool systematically crystallized the clinical elements of the RCCP and helped to standardize the training methods by creating a framework for providing feedback to learners that matches the items on the RCCP-FAT. The use of the RCCP-FAT to guide the training and mentoring of incoming group leaders is essential in the scaling and dissemination of a complex training method like the RCCP to ensure fidelity to the original evidence-based intervention. Full article

Alzheimer’s disease (AD) is a brain disorder that is more prevalent in developed nations and remains one of most intractable conditions so far. It is characterized by a gradual onset, a prolonged progression, and an unclear pathophysiology. At the present time, there are no effective treatments available for the disease. However, human neural stem cells (hNSCs) have the capacity to substitute lost neurons in a functional manner, strengthen synaptic networks that have been compromised, and repair the damaged brain. Due to the unavailability of restorative therapeutics, there is a significant global burden on the economy. When it comes to the treatment of neurodegenerative diseases, NSCs provide a potentially game-changing approach to treating Alzheimer’s disease. Through the delivery of trophic factors that promote the viability and regeneration of lost neurons in experimental animals suffering from neurodegenerative disorders, these treatments have the potential to facilitate beneficial recuperation. Positive restorative outcomes may be achieved in a variety of ways, including the replacement of lost cells, the combining of cells, the secretion of neurotrophic factors, the formation of endogenous stem cells, and transdifferentiation. Conversely, there are obstacles that need to be overcome before NSC-based treatments can be used in clinical settings. This review article discusses current developments in the use of neural stem cells (NSCs) for the treatment of Alzheimer’s disease (AD). In addition, we highlight the difficulties and opportunities that are involved with the use of neural stem cell transplant treatment for Alzheimer’s disease. Full article

Background: The heavily right-skewed data seen in recently reported Alzheimer’s disease (AD) clinical trials influenced treatment contrasts when data were analyzed via the typical mixed-effects model for repeated measures (MMRM). Methods: An MMRM analysis similar to what is commonly used in AD clinical trials was compared versus robust regression (RR) and the non-parametric Hodges–Lehman estimator (HL). Results: Results in simulated data patterned after AD trials showed that imbalance across treatment arms in the number of patients in the extreme right tail (those with rapid disease progression) frequently occurred. Each analysis method controlled Type I error at or below the nominal level. The RR analysis yielded smaller standard errors and more power than MMRM and HL. In data sets with appreciable imbalance in the number of rapid progressing patients, MMRM results favored the treatment arm with fewer rapid progressors. Results from HL showed the same trend but to a lesser degree. Robust regression yielded similar results regardless of the ratio of rapid progressors. Conclusions: Although more research is needed over a wider range of scenarios, it should not be assumed that MMRM is the optimal approach for trials in early Alzheimer’s disease. Full article

Endoplasmic reticulum (ER) stress is a detrimental cellular phenomenon in the cells and is activated by the accumulation of unfolded or misfolded proteins in the ER. The unfolded protein accumulation activates the unfolded protein response (UPR), an adaptive mechanism designed to mitigate cellular stress by enhancing the ER’s protein-folding capacity and protecting cells from apoptotic stimuli in neuroinflammation and neurodegenerative diseases. However, chronic ER stress and prolonged activation of the UPR can have adverse effects, including the activation of pro-apoptotic and inflammatory signaling pathways, which contribute to the development and progression of neurodegenerative disorders. Neurodegenerative diseases are complex and devastating conditions with underlying pathogenesis that are not fully understood. Genetic mutations leading to the accumulation of misfolded or phosphorylated tau proteins and amyloid-beta in the ER can induce ER stress, resulting in neuroinflammation and neuronal death. Several studies have reported the involvement of increased ER stress and UPR signaling proteins in the pathogenesis and progression of neurodegenerative diseases. Thus, inhibiting ER stress and neuroinflammation and targeting their associated signaling pathways represent a significant area of research interest. This review discusses the critical signaling molecules involved in ER stress, their mechanisms in the progression of neurodegenerative diseases, and the latest developments in the available ER stress inhibitors. Despite the extensive development of ER stress inhibitors over the years, only a limited number have been approved as pharmaceutical drugs. There remains a critical need for effective ER stress inhibitors to provide efficient treatments for neurodegenerative diseases, including Alzheimer’s disease. Full article

Episodic memory is affected early and is a basic indication of neurodegeneration especially for Alzheimer’s disease. The aim of this study was to examine whether adults with vascular risk factors are differentiated in their episodic memory performance from individuals with mild cognitive impairment (MCI). The episodic memory of adults diagnosed with MCI, adults with vascular risk factors (VRF; blood pressure, diabetes mellitus, or hypercholesterolemia), and healthy controls was assessed using the Doors and People test. Statistical processing included mediation analyses which were performed separately for the VRF and healthy control groups, and the MCI and healthy control groups. ANOVA was used for the MCI and VRF groups which were matched in age and education. ANOVA showed that the MCI adults had significantly lower performance than the VRF adults in verbal recall only, F (1, 83) = 9.541, p = 0.003, and η_p² = 0.10. A direct effect of diagnosis on verbal recall was found via mediation analysis as concerns individuals with MCI and healthy controls, b = 0.506, SE = 0.128, p < 0.001, and 95%CI: 0.221–0.771, in favor of the healthy controls. Concerning the VRF and healthy groups, a tendency of diagnosis to directly affect verbal recall was shown (α = 0.005) in favor of the healthy controls, b = 0.388, SE = 0.150, p = 0.010, and 95%CI: 0.043–0.720. In conclusion, it is supported that patients with MCI present deficit performance in verbal recall; in addition, the diagnostic category affects all the groups’ performance on the same condition. These results indicated that the verbal recall aspect of episodic memory can be a sensitive indicator that can differentiate healthy adults from adults with mild cognitive impairment and vascular risk factors, as well as the two pathological groups from each other. Full article

The entrance of cells into a permanent state of cell cycle arrest with the ability to resist apoptosis is termed “cellular senescence”. The accumulation of senescent cells within the body can lead to tissue aging and the dysfunction of organs. Whether due to external stressors or the passage of time, aging is an inevitable process that afflicts every living being. Current studies that investigate aging rely on the use of cells or rodent models. Although cells present a cost-effective and quick way to analyze aging, they lack the complexity of whole-body systems and therefore require the use of an in vivo model post-in vitro assays. The zebrafish, Danio rerio, presents a cost-effective model with quick development and large numbers of offspring. These fish share 70% similarity of their genes with humans, including genes known to be associated with human diseases, such as those diseases of aging and/or senescence, like Alzheimer’s disease. Major tissues and organs of humans are also found in these fish, and therefore, zebrafish can serve as a useful model when studying diseases, aging, Alzheimer’s disease, and other disorders. In this review, we will discuss some of the major senescence biomarkers and detection methods, as well as discuss how zebrafish models can be used for the study of aging and age-related disorders. Full article

The gut microbiota (GM) communicates with the brain via biochemical signaling constituting the gut–brain axis, which significantly regulates the body’s physiological processes. The GM dysbiosis can impact the digestive system and the functioning of the central nervous system (CNS) linked to the onset of neurodegenerative diseases. In this review, the scientific data compiled from diverse sources primarily emphasize the neuropathological characteristics linked to the accumulation of modified insoluble proteins (such as β-amyloid peptides and hyperphosphorylated tau proteins) in Alzheimer’s disease (AD) and the potential impact of gut microbiota (GM) on AD susceptibility or resilience. The specific GM profile of human beings may serve as an essential tool for preventing or progressing neurodegenerative diseases like AD. This review focuses mainly on the effect of gut microfauna on the gut–brain axis in the onset and progression of AD. The GM produces various bioactive molecules that may serve as proinflammatory or anti-inflammatory signaling, contributing directly or indirectly to the repression or progression of neurodegenerative disorders by modulating the response of the brain axis. Human studies must focus on further understanding the gut–brain axis and venture to clarify microbiota-based therapeutic strategies for AD. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms due to the loss of dopamine-producing neurons and the presence of Lewy bodies in the brain. While current treatments such as dopamine replacement with levodopa and deep brain stimulation mainly manage symptoms and do not stop disease progression, recent advancements in nanomedicine provide promising new therapy options. These include drug-loaded nanocarriers that improve drug delivery to the brain, enhancing effectiveness and reducing side effects. This review explores novel nanomedical approaches like solid lipid nanocarriers (SLNs), which could improve drug profiles and decrease the adverse effects seen with traditional PD treatments. Additionally, it discusses the challenge of crossing the blood–brain barrier, which is crucial for treating central nervous system disorders, and how nanocarriers facilitate targeted brain delivery. Despite these advancements, the review emphasizes more research into the safety and long-term impacts of nanomedicine in PD, highlighting the challenge of moving these treatments from lab to clinical use. Full article