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Yesong Shin,1 Chungam Choi,2 Eun Sil Oh,2,3 Choon Ok Kim,2 Kyungsoo Park,1 Min Soo Park2– 4 1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; 2Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea; 3Department of Pharmaceutical Medicine and Regulatory Science, Graduate Inter Program, Yonsei University College of Medicine, Seoul, Korea; 4Department of Pediatrics, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Min Soo Park, Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea, Tel +82-2-2228-0400, Fax +82-31-787-4045, Email minspark@yuhs.acPurpose: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics.Patients and Methods: An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference.Results: Maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC0-96h) of evogliptin with and without co-administration of rifampicin were compared. Reference and test Cmax and AUC0-96h values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration.Conclusion: Rifampicin decreased the AUC0-96h of evogliptin by 61.8% without significantly affecting Cmax. The mechanism underlying the decrease in AUC0-96h is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.Keywords: drug–drug interaction, DPP-4 inhibitor, CYP3A inducer, evogliptin, rifampicin

Heejeong Hong,1 Hyun-Kuk Song,1 Bohee Jang,1 Eunhye Park,1 Dong Soo Han,2 Seong-Eun Kim,3 Eok-Soo Oh1 1Department of Life Sciences, Ewha Womans University, Seoul, South Korea; 2Department of Internal Medicine, Hanyang University College of Medicine, Guri, South Korea; 3Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Institute, Seoul, South KoreaCorrespondence: Eok-Soo OhDepartment of Life Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemoon-Gu, Seoul, 03760, South KoreaTel +82-2-3277-3761Fax +82-2-3277-3760Email OhES@ewha.ac.krIntroduction: Syndecan-2 expression is elevated during chronic inflammation and cancer development, and its shedding is observed in cancer patients. However, it remained unknown whether inflammation triggers syndecan-2 shedding.Methods: The colitis model was produced in C57BL/6 mice by oral administration of 2– 3% dextran sulfate sodium (DSS) in the drinking water. Syndecan-2 and MMP-7 expression levels in tissues and cells were detected by real-time PCR, Western blotting, and immunohistochemistry. Shed syndecan-2 levels were detected by slot blotting. For tissue culture, colon tissues were divided into proximal, transverse, and distal parts, and incubated in culture media.Results: In C57BL/6 mice with DSS-induced colitis, syndecan-2 shedding began to increase after week 12 of chronic inflammation and continued to increase at week 15. The level of shed syndecan-2 correlated with the colocalization of syndecan-2 and MMP-7 in distal colon tissues. The mRNA expression of IL-6 was increased specifically in trans-distal colon tissues from weeks 9 to 15. IL-6 induced syndecan-2 expression and shedding and MMP-7 expression in ex vivo-cultured distal colon tissues and adenoma cell lines derived from the distal colon. IL-6 treatment induced STAT3 phosphorylation and MMP-7 expression in DLD-1 cells. The application of MMP-7 to ex vivo-cultured colon tissues increased the shedding of syndecan-2 to the culture medium.Conclusion: Our findings suggest that chronic inflammation induces syndecan-2 shedding via the site-specific colocalization of syndecan-2 with MMP-7 in the distal colon.Keywords: chronic inflammation, syndecan-2, MMP-7, shedding

Choon Ok Kim,1 Eun Sil Oh,2 Hohyun Kim,3 Min Soo Park1,4 1Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul, 2Department of Pharmaceutical Medicine and Regulatory Sciences, College of Medicine and Pharmacy, Yonsei University, Incheon, 3Korea Medicine Research Institute, Inc., Seongnam, 4Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea Abstract: To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration–time curve during the dose interval at steady state (AUCt,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism. Keywords: glimepiride, rosuvastatin, pharmacokinetics, SLCO1B1, CYP2C9

Choon Ok Kim,1 Eun Sil Oh,2 Chungam Choi,1 Yeonjoo Kim,3 Sera Lee,4 Semi Kim,4 Min Soo Park1,5 1Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul, 2Department of Pharmaceutical Medicines and Regulatory Science, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, 3Chong Kun Dang Clinical Research, Chong Kun Dang Pharmaceutical Corp., 4Chong Kun Dang Research Institute, Chong Kun Dang Pharmaceutical Corp., 5Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea Abstract: CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (Cmax) at 5–6 h post-dose, and had a long terminal half-life ranging between 40–70 h. The area under the plasma concentration–time curve (AUC) and Cmax increased with the dose, however, Cmax and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%–83%) was observed at 6–8 h post-dose. A sigmoid Emax model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC50 of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity. Keywords: cholesteryl ester transfer protein inhibitor, CKD-519, pharmacokinetics, pharma­codynamics

Kathryn B Holroyd,1 Lisa Fosdick,2 Gwenn S Smith,1 Jeannie-Marie Leoutsakos,1 Cynthia A Munro,1 Esther S Oh,1 Kristen E Drake,2 Paul B Rosenberg,1 William S Anderson,1 Stephen Salloway,3–5 J Cara Pendergrass,6 Anna D Burke,7 David A Wolk,8 David F Tang-Wai,9–11 Francisco A Ponce,12 Wael F Asaad,13,14 Marwan N Sabbagh,15 Michael S Okun,16 Gordon Baltuch,17 Kelly D Foote,18 Steven D Targum,2,6 Andres M Lozano,10,11 Constantine G Lyketsos1 1Johns Hopkins University Memory and Alzheimer's Treatment Center, Baltimore, MD, 2Functional Neuromodulation Ltd, Minneapolis, MN, 3Department of Neurology, Butler Hospital, 4Department of Neurology, Rhode Island Hospital, 5Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, 6Clintara LLC, Boston, MA, 7Banner Alzheimer's Institute, Phoenix, AZ, 8Penn Memory Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; 9Department of Neurology, 10Department of Neurosurgery, University of Toronto, 11Division of Neurology, University Health Network Memory Clinic, Toronto, ON, Canada; 12Division of Neurological Surgery, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ, 13Department of Neurosurgery, Rhode Island Hospital, 14Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, RI, 15Banner Sun Health Research Institute, Sun City, AZ, 16Center for Movement Disorders and Neurorestoration, Department of Neurology, University of Florida – Gainsville, Gainsville, FL, 17Center for Functional and Restorative Neurosurgery, University of Pennsylvania, Philadelphia, PA, 18Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, University of Florida, Gainsville, FL, USA Background: There are currently few available treatments and no cure for Alzheimer disease (AD), a growing public health burden. Animal models and an open-label human trial have indicated that deep brain stimulation (DBS) of memory circuits may improve symptoms and possibly slow disease progression. The ADvance trial was designed to examine DBS of the fornix as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebo-controlled, delayed-start, multicenter clinical trial conducted at six sites in the US and one site in Canada. Eighty-five subjects initially consented to be screened for the trial. Of these, 42 subjects who met inclusion and exclusion criteria were implanted with DBS leads anterior to the columns of the fornix bilaterally. They were randomized 1:1 to DBS “off” or DBS “on” groups for the initial 12 months of follow-up. After 1 year, all subjects will have their devices turned “on” for the remainder of the study. Postimplantation, subjects will return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary outcome measures include Alzheimer's Disease Assessment Scale – cognitive component (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography. This report details the study methods, baseline subject characteristics of screened and implanted participants, and screen-to-baseline test–retest reliability of the cognitive outcomes. Results: Implanted subjects had a mean age of 68.2 years, were mostly male (55%), and had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD, 5.2) and 3.9 (SD, 1.6), respectively. There were no significant differences between screened and implanted or nonimplanted subjects on most demographic or clinical assessments. Implanted subjects had significantly lower (better) ADAS-cog-11 (17.5 vs 21.1) scores, but did not differ on CDR-SB. Scores on the major outcome measures for the trial were consistent at screening and baseline. Conclusion: ADvance was successful in enrolling a substantial group of patients for this novel application of DBS, and the study design is strengthened by rigorous subject selection from seven sites, a double-blind placebo-controlled design, and extensive open-label follow-up. Keywords: deep brain stimulation, Alzheimer disease, fornix, methods, clinical trials

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

The role of amyloid-β (Aβ in the neurodegeneration of Alzheimer's disease remains controversial, to a large extent because of the lack of robust neurodegeneration in mouse models of AD. To address this question, we examined the effects of Aβ antibodies in the recently described monoaminergic (MAergic) axonal degeneration in AβPPswe/PS1dE9 mice. To determine if Aβ accumulation is directly involved in degeneration of MAergic axons, we examined the effects of passive anti-Aβ antibody (7B6) administration on Aβ pathology and MAergic degeneration in AβPPswe/PS1dE9 mice. Injections of monoclonal antibody (mAb) 7B6 into mice (6 to 9 months of age) resulted in a modest reduction of Aβ load in the brains of AβPPswe/PS1dE9 mice. In addition, 7B6 treated AβPPswe/PS1dE9 mice had significantly higher densities of MAergic axons in both cortex and in hippocampus as compared to untreated mutant mice. For example, 7B6 treated mice showed almost 2-fold greater densities of serotonergic (5-HT) axons in the cortex compared to saline treated mice. Similar findings were observed in the catecholaminergic (TH) axons. Our results demonstrate that lowering of Aβ levels via passive Aβ immunotherapy ameliorates ongoing degenerative processes, supporting a causal link between Aβ and neurodegeneration. [ABSTRACT FROM AUTHOR]

Plasma amyloid-β (Aβ) level could be useful as a non-invasive biomarker in Alzheimer's disease research. We compared a multiplex electrochemiluminescence detection method with a well established ELISA method for plasma Aβ quantification. Compared to the ELISA method, the electrochemiluminescence detection method demonstrates a statistically significant, but modest correlation. The reasons for this may include the differences in the affinities of antibodies, and purity and source of Aβ peptides used as standards. However, the advantages of electrochemiluminescence detection technology include short processing time and small sample volume. This comparison demonstrates the need for a further study in optimizing this system. [ABSTRACT FROM AUTHOR]

PURPOSE: Early detection of oral cancer is crucial in improving survival rate. To improve early detection, the use of a dilute acetic acid rinse and observation under a chemiluminescent light (ViziLite; Zila Pharmaceuticals, Phoenix, AZ) has been recommended. However, to date, the contributions of the individual components of the system have not been studied. The present study was done to investigate the efficacy of the individual components of the ViziLite system in providing improved visualization of early oral mucosal lesions. PATIENTS AND METHODS: A total of 100 patients, 39 males and 61 females, age 18 to 93 years (mean age, 44 years), who presented to the Virginia Commonwealth University School of Dentistry for dental screening were examined. There were 58 Caucasians, 29 African-Americans, 5 Hispanics, 6 Asians, and 2 of mixed ethnicity. Thirty-five patients smoked, 53 used alcohol, and 25 both smoked and drank. After written consent, the oral cavity was examined under incandescent light for soft tissue abnormalities. After 1-minute rinse with 1% acetic acid, the mouth was re-examined for additional mucosal abnormalities. Then, the mouth was examined once again using the ViziLite system's chemiluminescent light. Any lesions detected by these 3 examinations that were clinically undiagnosable were brush biopsied (Oral CDx) for determination of cellular representation. RESULTS: In the original examination of the 100 patients, 57 clinically diagnosable benign lesions (eg, linea alba, leukoedema) and 29 clinically undiagnosable lesions were detected. After the rinse, 6 additional diagnosable lesions (linea alba) and 3 undiagnosable lesions were found. No additional lesions were detected with the chemiluminescent light. Of the 32 undiagnosable lesions that were brush biopsied, 2 were positive for atypical cellular characterization and warranted further investigation with a scalpel biopsy. Neither of these lesions was found to be premalignant or malignant. CONCLUSION: Although the acid rinse accentuated some lesions, the overall detection rate was not significantly improved. The chemiluminescent light produced reflections that made visualization more difficult and thus was not beneficial.Copyright © 2007 by the American Association of Oral and Maxillofacial Surgeons [ABSTRACT FROM AUTHOR]

The National Institute on Aging (NIA) plays a pivotal role in advancing scientific research, developing training and the science workforce, and promoting public health initiatives. However, the benefits of the NIA's work have not been equally distributed among all older adult population groups, highlighting persistent disparities in chronic illness burden and access to healthcare and research. As the NIA commemorates its 50th anniversary, this milestone presents an opportunity to reflect on its consequential initiatives and accomplishments while also strategizing for the robust inclusion of underrepresented and minoritized populations and the future health of our Nation's older adult population. Disparities in Alzheimer's disease and related dementias among four minoritized and racialized groups are highlighted, as well as the critical need to recruit and retain investigators from these populations. Three trans-NIA training, outreach, and pipeline initiatives are described as having elevated the profile of aging research across the nation, particularly among minoritized and ethnic groups, and have reached thousands of individuals interested in aging research. Leaders and healthcare advocates argue that efforts to reduce health disparities cannot be fully achieved without successfully addressing the underrepresentation of minoritized leaders in healthcare and research. Racism, xenophobia, discrimination, and separation deprive our nation and the scientific community of the breadth of talent, expertise, and perspectives needed to address racialized/minoritized health inequities. To all the staff at the NIA, past and present, may you continue to be proud of the work you do, the Institute you represent, and the difference you make. Happy 50th Anniversary!, (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We describe the novel HLA-DPB1*01:01:15 allele found in a female African American., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Delirium and dementia are common causes of cognitive impairment in older adults. They are distinct but interrelated. Delirium, an acute confusional state, has been linked to the chronic and progressive loss of cognitive ability seen in dementia. Individuals with dementia are at higher risk for delirium, and delirium itself is a risk factor for incident dementia. Additionally, delirium in individuals with dementia can hasten underlying cognitive decline. In this review, we summarize recent literature linking these conditions, including epidemiological, clinicopathological, neuroimaging, biomarker, and experimental evidence supporting the intersection between these conditions. Strategies for evaluation and diagnosis that focus on distinguishing delirium from dementia in clinical settings and recommendations for delirium prevention interventions for patients with dementia are presented. We also discuss studies that provide evidence that delirium may be a modifiable risk factor for dementia and consider the impact of delirium prevention interventions on long-term outcomes., Competing Interests: None declared., (Thieme. All rights reserved.)

Neurodegenerative diseases (NDs) can be difficult to precisely characterize and monitor as they present complex and overlapping signs despite affecting different neural circuits. Neuropsychological tests are important tools for assessing signs, but only considering patient-generated output can limit insight. Here, we present an improvement to the neuropsychological test evaluation paradigm by deeply characterizing patient interaction and behavior during tests based on multiple perspectives alongside typically evaluated output by performing multi-modal analysis of eye movement and speech data. Using the well-known Stroop Test, we compare behaviors of healthy controls to patients with Alzheimer's Disease (AD), Mild Cognitive Impairment, Parkinson's Disease (PD), and secondary Parkinsonism. We maximize accessibility and reproducibility by automatically extracting metrics, including eye motor behavior, speech patterns, and multimodal interplay, with almost no human input required. We find many metrics including increased horizontal saccade distances sensitive to all NDs, delayed task initiation in AD, response error patterns and blinking patterns that differ between AD and PD. Our metrics show both significantly different distributions between disease groups and simultaneous correlation with the MoCA and MDS-UPDRS-III clinical rating scales. Our findings show the utility of incorporating several perspectives into one output representation, as our metric breadth creates unique sign profiles that quantify and visualize a patient's dysfunction. These metrics provide much better sign characterization between diseases and correlation with disease severity than traditional Stroop measures. This methodology offers the potential to expand its application to other traditional neuropsychological tests, shifting the paradigm in diagnostic precision for NDs and advancing patient care., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Delirium commonly occurs in older adults following surgery; although its pathophysiology is not fully understood, underlying neurodegeneration is a risk factor., Objective: Examine the association of preoperative levels of markers of neuronal damage, neurofilament light (NfL) and phosphorylated tau (p-tau) 181 , with postoperative delirium., Methods: Preoperative cerebrospinal fluid (CSF) and plasma were obtained from 158 patients undergoing hip fracture repair and enrolled in the clinical trial "A STrategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients." Delirium diagnosis was adjudicated by a consensus panel. The association of plasma and CSF NfL and p-tau 181 levels with delirium incidence and severity were examined for the overall cohort and for a subgroup (n = 134) of patients without dementia., Results: Patients who developed delirium were older, had lower Mini-Mental State Exam score, higher Clinical Dementia Rating and Geriatric Depression Scale scores at baseline; the overall incidence of delirium was 37.6% and 31.1% for the subgroup without dementia. Plasma and CSF p-tau 181 levels were not associated with delirium incidence or severity. CSF NfL levels were significantly associated with delirium severity, but not with incidence in the overall cohort. In the subgroup of patients without dementia, CSF NfL levels were significantly associated with increased odds of delirium incidence (odds ratio 4.74, 95% confidence level 1.21-18.59, P = 0.03) adjusted for age, sex, and Clinical Dementia Rating., Conclusions: CSF NfL was significantly associated with delirium incidence and severity in patients without dementia undergoing hip fracture repair. Results confirm prior studies suggesting NfL as an important marker of delirium risk and supports an association between pre-existing axonal injury and delirium. These results highlight delirium vulnerability in older hip fracture patients, even when clinical dementia is not identified., (Copyright © 2024 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Delirium, an acute brain dysfunction, is proposed to be highly prevalent in clinical care and shown to significantly increase the risk of mortality and dementia., Objectives: To report on the global prevalence of clinically documented delirium and delirium-related clinical practices in wards caring for paediatric and adult patients in healthcare facilities., Design: A prospective, cross-sectional, 39-question survey completed on World Delirium Awareness Day, 15 March 2023., Participants: Clinicians or researchers with access to clinical data., Main Outcome and Measure: The primary outcome was the prevalence of clinically documented delirium at 8:00 a.m. (4 h) and 8:00 p.m. (±4 h). Secondary outcomes included delirium-related care practices and barriers to use. Descriptive statistics were calculated and multilevel modelling was completed., Results: 1664 wards submitted surveys from 44 countries, reporting on delirium assessments at 8:00 a.m. (n = 36 048) and 8:00 p.m. (n = 32 867); 61% reported use of validated delirium assessment tools. At 8:00 a.m., 18% (n = 2788/15 458) and at 8:00 p.m., 17.7% (n = 2454/13 860) were delirium positive. Top prevention measures were pain management (86.7%), mobilisation (81.4%) and adequate fluids (80.4%). Frequently reported pharmacologic interventions were benzodiazepines (52.7%) and haloperidol (46.2%). Top barriers included the shortage of staff (54.3%), lack of time to educate staff (48.6%) and missing knowledge about delirium (38%)., Conclusion and Relevance: In this study, approximately one out of five patients were reported as delirious. The reported high use of benzodiazepines needs further evaluation as it is not aligned with best-practice recommendations. Findings provide a benchmark for future quality improvement projects and research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Dementia, or major neurocognitive disorder, is defined as a decline in 1 or more cognitive domains that causes impairment in everyday function. Alzheimer disease is the most common type of dementia in the United States, with an estimated 6.9 million adults who have Alzheimer disease and are 65 years or older. This article discusses the latest findings in preventing cognitive decline. It also discusses dementia screening, diagnosis, treatment, and the quality of life for persons with dementia and their caregivers., Competing Interests: Disclosures: All relevant financial relationships have been mitigated. Disclosure forms are available with the article online.

Purpose: Regional nodal irradiation (RNI) to the axilla and supraclavicular area presents distinct toxicities, such as lymphedema and shoulder stiffness, compared with whole-breast irradiation. There is insufficient evidence on the safety of dose-escalation in hypofractionated RNI. We aimed to evaluate and compare toxicity rates in patients with breast cancer who received hypofractionated RNI with and without dose-escalation., Methods and Materials: We retrospectively analyzed 381 patients with breast cancer treated with hypofractionated RNI between March 2015 and February 2017. Patients received either the standard-dose to the regional nodal area (43.2 Gy/16 fx; 48.7 Gy 3.5 equivalent dose [EQD2], 2 Gy equivalent dose with α/β= 3.5 Gy) or dose-escalation with a median dose of 54.8 Gy 3.5 EQD2 (range, 51.7-60.9 Gy 3.5 EQD2), depending on clinical and pathologic nodal stage. Toxicity rates of lymphedema and shoulder stiffness were assessed, and statistical analyses were conducted to identify associated factors., Results: The median follow-up time was 32.3 months (5.7-47.0 months). After radiation therapy, 71 (18.6%) patients developed lymphedema, and 48 (12.6%) developed shoulder stiffness. Patients who received dose-escalation exhibited significantly higher rates of lymphedema (32.1% vs 14.8%; odds ratio, 2.72, P = .0004) and shoulder stiffness (23.8% vs 9.4%; odds ratio, 2.01, P = .0205) compared with the standard-dose group. Moreover, dose-escalation showed a tendency to increase the severity of lymphedema and shoulder stiffness., Conclusions: Patients who received dose-escalation in hypofractionated RNI face a higher risk of developing lymphedema and shoulder stiffness compared with those who received standard-dose hypofractionated RNI. Therefore, it is crucial to implement close and frequent monitoring for early detection, along with timely rehabilitation interventions for these patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Tangeretin, a natural polymethoxyflavone compound, possesses potent anti-inflammatory activity that improves respiratory inflammation in chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying the anti-COPD effects of tangeretin remain unclear. In this study, we aimed to investigate the key molecular mechanisms by which tangeretin suppresses COPD-related inflammatory responses., Methods: We conducted the investigation in phorbol-12-myristate-13-acetate (PMA)-stimulated human airway epithelial cells ( in vitro ) and cigarette smoke (CS)/lipopolysaccharide (LPS)-exposed mice ( in vivo )., Results: Tangeretin decreased the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and mucin 5AC (MUC5AC), by suppressing early growth response 1 (EGR1) expression in vitro . Tangeretin and EGR1 small interfering ribonucleic acid (siRNA) combination showed a synergistic reduction in MUC5AC and TNF-α secretion. Tangeretin administration significantly inhibited the levels of reactive oxygen species (ROS) production, elastase activity, TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1) secretion, and macrophage and neutrophil numbers in the bronchoalveolar lavage fluid of CS/LPS-exposed mice. Tangeretin also prevented CS/LPS-induced abnormal pathological changes and excessive MUC5AC and EGR1 expression in lung tissue., Conclusion: Comprehensively, tangeretin inhibits the lung inflammatory response associated with COPD by reducing EGR1 expression in PMA-induced human epithelial cells and in a CS/LPS-stimulated mouse model. This study shows that tangeretin has anti-COPD properties and can be a promising alternative (or complementary) treatment for inflammatory lung disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Importance: Dementia and hearing loss are prevalent and represent public health priorities, but little is known about the prevalence of hearing loss among persons living with dementia at a population level., Objective: To estimate the prevalence of hearing loss and hearing aid use among a nationally representative sample of persons living with dementia., Design, Setting, and Participants: In this cross-sectional study, we analyzed data from Medicare beneficiaries who participated in round 11 of the National Health and Aging Trends Study (NHATS). The analytic sample included participants who had complete audiometric data and a dementia classification, and survey weights were applied to yield nationally representative estimates. Data were collected from June to November 2021, and analyzed from October 12, 2023, to February 27, 2024., Exposures: Audiometric measures of hearing loss and self-reported hearing aid use., Main Outcomes and Measures: National prevalence estimates of possible and probable dementia and hearing loss were estimated by applying NHATS survey weights of sex and age to the population aged 71 years or older based on the US Census Bureau's 2020 American Community Survey data., Results: The analytic sample comprised 2613 NHATS participants (74.6% aged 71-79 years and 25.4% aged ≥80 years; 52.9% female). Overall prevalence of hearing loss among participants with dementia was estimated at 79.4% (95% CI, 72.1%-85.3%). The prevalence of hearing loss increased with age, from 61.1% (95% CI, 37.7%-80.2%) among participants aged 71 to 74 years to 94.2% (95% CI, 88.8%-97.0%) among those aged 85 years or older. Among participants with hearing loss, 21.7% (95% CI, 16.2%-28.3%) reported hearing aid use., Conclusions and Relevance: In this cross-sectional study, the findings suggest that hearing loss is highly prevalent among individuals with dementia, with a low prevalence of hearing aid use. These findings reveal a potential opportunity for intervention.

Background: Hearing loss is prevalent and consequential but under-diagnosed and managed. The Medicare Annual Wellness Visit (AWV) health risk assessment elicits patient-reported hearing concerns but whether such information affects documentation, diagnosis, or referral is unknown., Methods: We use 5 years of electronic medical record (EMR) data (2017-2022) for a sample of 13,776 older primary care patients. We identify the first (index) AWV indication of hearing concerns and existing and subsequent hearing loss EMR diagnoses (visit diagnoses or problem list diagnoses) and audiology referrals. For a 20% random sample of AWV notes (n = 474) we compared hearing loss EMR diagnoses to documentation of (1) hearing concerns, (2) hearing loss/aid use, and (3) referrals for hearing care., Results: Of 3845 (27.9%) older adults who identified hearing concerns (mean age 79.1 years, 57% female, 75% white) 24% had an existing hearing diagnosis recorded. Among 474 patients with AWV clinical notes reviewed, 90 (19%) had an existing hearing loss diagnosis. Clinicians were more likely to document hearing concerns or hearing loss/aid use for those with (vs. without) an existing EMR diagnosis (50.6% vs. 35.9%, p = 0.01; 68.9% vs. 37.5%, p < 0.001, respectively). EMR diagnoses of hearing loss were recorded for no more than 40% of those with indicated hearing concerns. Among those without prior diagnosis 38 (9.9%) received a hearing care referral within 1 month. Subgroup analysis suggest greater likelihood of documenting hearing concerns for patients age 80+ (OR:1.51, 95% confidence interval [CI]: 1.03, 2.19) and decreased likelihood of documenting known hearing loss among patients with more chronic conditions (OR: 0.49, 95% CI: 0.27, 0.9), with no differences observed by race., Conclusion: Documentation of hearing loss in EMR and AWV clinical notes is limited among older adults with subjective hearing concerns. Systematic support and incorporation of hearing into EMR and clinical notes may increase hearing loss visibility by care teams., (© 2024 The Author(s). Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Plasmodesmata (PDs) are intercellular organelles carrying multiple membranous nanochannels that allow the trafficking of cellular signalling molecules. The channel regulation of PDs occurs dynamically and is required in various developmental and physiological processes. It is well known that callose is a critical component in regulating PD permeability or symplasmic connectivity, but the understanding of the signalling pathways and mechanisms of its regulation is limited. Here, we used the reverse genetic approach to investigate the role of C-type lectin receptor-like kinase 1 (CLRLK1) in the aspect of PD callose-modulated symplasmic continuity. Here, we found that loss-of-function mutations in CLRLK1 resulted in excessive PD callose deposits and reduced symplasmic continuity, resulting in an accelerated gravitropic response. The protein interactome study also found that CLRLK1 interacted with actin depolymerizing factor 3 (ADF3) in vitro and in plants. Moreover, mutations in ADF3 result in elevated PD callose deposits and faster gravitropic response. Our results indicate that CLRLK1 and ADF3 negatively regulate PD callose accumulation, contributing to fine-tuning symplasmic opening apertures. Overall, our studies identified two key components involved in the deposits of PD callose and provided new insights into how symplasmic connectivity is maintained by the control of PD callose homoeostasis., (© 2024 The Author(s). Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Allergic asthma is a major health burden on society as a chronic respiratory disease characterized by inflammation and muscle tightening around the airways in response to inhaled allergens. Daphne kiusiana Miquel is a medicinal plant that can suppress allergic airway inflammation; however, its specific molecular mechanisms of action are unclear. In this study, we aimed to elucidate the mechanisms by which D. kiusiana inhibits allergic airway inflammation. We evaluated the anti-inflammatory effects of the ethyl acetate (EA) fraction of D. kiusiana and its major compound, daphnetin, on murine T lymphocyte EL4 cells stimulated with phorbol 12-myristate 13-acetate and ionomycin in vitro and on asthmatic mice stimulated with ovalbumin in vivo. The EA fraction and daphnetin inhibited T-helper type 2 (Th2) cytokine secretion, serum immunoglobulin E production, mucus secretion, and inflammatory cell recruitment in vivo. In vitro, daphnetin suppressed intracellular Ca 2+ mobilization (a critical regulator of nuclear factor of activated T cells) and functions of the activator protein 1 transcription factor to reduce interleukin (IL)-4 and IL-13 expression. Daphnetin effectively suppressed the IL-4/-13-induced activation of Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6) signaling in vitro and in vivo, thereby inhibiting the expression of GATA3 and PDEF, two STAT6-target genes responsible for producing Th2 cytokines and mucins. These findings indicate that daphnetin suppresses allergic airway inflammation by stabilizing intracellular Ca 2+ levels and subsequently inactivating the JAK/STAT6/GATA3/PDEF pathway, suggesting that daphnetin is a promising alternative to existing asthma treatments., Competing Interests: Declaration of competing interest None: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Delirium is an acute brain dysfunction associated with an increased risk of mortality and future dementia., Objectives: To describe the prevalence of clinically documented delirium in the United States on World Delirium Awareness Day 2023., Methods: This is a sub-analysis of a prospective, cross-sectional, online, international survey. All health care settings were eligible, with the exception of operating rooms and outpatient clinics. Health care clinicians, administrators, and researchers completed the survey. The primary outcome was the prevalence of clinically documented delirium at 8:00 a.m. and 8:00 p.m. on March 15, 2023. Secondary outcomes were related to health care delivery. Descriptive statistics are reported. Differences between unit types (non-intensive care unit vs intensive care unit) were examined for all outcomes., Results: Ninety-one hospital units reported on 1318/1213 patients. The prevalence of clinically documented delirium was 16.4% (n = 216/1318) at 8:00 a.m. and 17.9% (n = 217/1213) at 8:00 p.m. (P = 0.316) and significantly differed between age groups, reported discipline, unit, and hospital types. Significant differences were identified between non-intensive care unit and intensive care unit settings in the use of delirium-related protocols, nonpharmacologic and pharmacologic management, educational processes, and barriers to evidence-based delirium care., Conclusions: To our knowledge, this is the first epidemiologic survey of clinically documented delirium across two time points in the United States. Delirium remains a significant burden and challenge for health care systems. The high percentage of units using delirium management protocols suggests administrator and clinician awareness of evidence-based strategies for its detection and mitigation. We provide recommendations for future studies and quality improvement projects to improve clinical recognition and management of delirium., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19 , CYP2D6 , CYP3A4 , and ABCB1 , and its effect on these outcomes., Methods: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects., Results: Eleven cis- SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain ( q =0.027) and serum concentrations of ESC adj ( q <0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESC adj concentrations. CITs did not indicate that these effects were epigenetically mediated., Discussion: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored., Competing Interests: Dr. Benicio N. Frey has no conflicts to disclose. Dr. Roumen V. Milev has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE Pharmaceuticals, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes of Health Research (CIHR), Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute (OBI), and Ontario Mental Health Foundation (OMHF). Dr. Sagar V. Parikh has received research support or consulting income from Aifred, Assurex (Myriad), Janssen, Mensante, Otsuka, Sage, and Takeda. Dr. Stefanie Hassel has no conflicts of interest to disclose. Dr. Pierre Blier received honoraria for participation in advisory boards, giving lectures, and/or expert consultation from Allergan, Bristol Myers Squibb, Janssen, Lundbeck, Otsuka, Pierre Fabre Medicaments, Pfizer and Sunovion; he received grants from Allergan, Janssen, and Lundbeck/Otsuka. Dr. Faranak Farzan received funding from Michael Smith Foundation for Health Research, Natural Sciences and Engineering Research Council of Canada Discovery, and Canadian Institutes of Health Research. Dr. Raymond W. Lam has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Abbvie, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Boehringer-Ingelheim, Canadian Institutes of Health Research (CIHR), Canadian Network for Mood and Anxiety Treatments, Carnot, Healthy Minds Canada, Janssen, Lundbeck, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute (OBI), Otsuka, Pfizer, Unity Health, and VGH-UBCH Foundation. Dr. Gustavo Turecki has received an Investigator-initiated grant from Pfizer Canada, and honoraria from Bristol-Meyers Squibb Canada and Janssen Canada. Dr. Susan Rotzinger has received grant funding from the Ontario Brain Institute (OBI), and Canadian Institutes of Health Research (CIHR), and holds a patent Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Dr. Stefan Kloiber has received honorarium for past consultation from EmpowerPharm. Dr. Sidney H. Kennedy has received research funding or honoraria from the following sources: Abbott, Alkermes, Allergan, Bristol-Myers Squibb (BMS), Brain Canada, Canadian Institutes for Health Research (CIHR), Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute (OBI), Ontario Research Fund (ORF), Otsuka, Pfizer, Servier, Sunovion and holds stock in Field Trip Health. Dr. Daniel J. Müller reports to be a co-investigator on two pharmacogenetic studies where genetic test kits were provided as in-kind contributions by Myriad Neuroscience. All other authors report no conflicts of interest related to this work., (Thieme. All rights reserved.)

Objective: The surgical population is ageing and often frail. Frailty increases the risk for poor post-operative outcomes such as delirium, which carries significant morbidity, mortality and cost. Frailty is often measured in a binary manner, limiting pre-operative counselling. The goal of this study was to determine the relationship between categorical frailty severity level and post-operative delirium., Methods: We performed an analysis of a retrospective cohort of older adults from 12 January 2018 to 3 January 2020 admitted to a tertiary medical center for elective surgery. All participants underwent frailty screening prior to inpatient elective surgery with at least two post-operative delirium assessments. Planned ICU admissions were excluded. Procedures were risk-stratified by the Operative Stress Score (OSS). Categorical frailty severity level (Not Frail, Mild, Moderate, and Severe Frailty) was measured using the Edmonton Frail Scale. Delirium was determined using the 4 A's Test and Confusion Assessment Method-Intensive Care Unit., Results: In sum, 324 patients were included. The overall post-operative delirium incidence was 4.6% (15 individuals), which increased significantly as the categorical frailty severity level increased (2% not frail, 6% mild frailty, 23% moderate frailty; P < 0.001) corresponding to increasing odds of delirium (OR 2.57 [0.62, 10.66] mild vs. not frail; OR 12.10 [3.57, 40.99] moderate vs. not frail)., Conclusions: Incidence of post-operative delirium increases as categorical frailty severity level increases. This suggests that frailty severity should be considered when counselling older adults about their risk for post-operative delirium prior to surgery., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Clubroot, caused by Plasmodiophora brassicae , is one of the diseases that causes major economic losses in cruciferous crops worldwide. Although prevention strategies, including soil pH adjustment and crop rotation, have been used, the disease's long persistence and devastating impact continuously remain in the soil. CR varieties were developed for clubroot-resistant (CR) Chinese cabbage, and 'Akimeki' is one of the clubroot disease-resistant cultivars. However, recent studies have reported susceptibility to several Korean pathotypes in Akimeki and the destruction of the resistance to P. brassicae in many Brassica species against CR varieties, requiring the understanding of more fine-tuned plant signaling by fungal pathogens. In this study, we focused on the early molecular responses of Akimeki during infection with two P. brassicae strains, Seosan (SS) and Hoengseong2 (HS2), using RNA sequencing (RNA-seq). Among a total of 2358 DEGs, 2037 DEGs were differentially expressed following SS and HS2 infection. Gene ontology (GO) showed that 1524 and 513 genes were up-regulated following SS and HS2 inoculations, respectively. Notably, the genes of defense response and jasmonic acid regulations were enriched in the SS inoculation condition, and the genes of water transport and light intensity response were enriched in the HS2 inoculation condition. Moreover, KEGG pathways revealed that the gene expression set were related to pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) mechanisms. The results will provide valuable information for developing CR cultivars in Brassica plants.

This study explores the 24-h rhythmic cycle of protein O-GlcNAcylation within the brain and highlights its crucial role in regulating the circadian cycle and neuronal function based on zebrafish as an animal model. In our experiments, disruption of the circadian rhythm, achieved through inversion of the light-dark cycle or daytime melatonin treatment, not only impaired the rhythmic changes of O-GlcNAcylation along with altering expression patterns of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in zebrafish brain but also significantly impeded learning and memory function. In particular, circadian disruption affected rhythmic expression of protein O-GlcNAcylation and OGT in the nuclear fraction. Notably, the circadian cycle induces rhythmic alterations in O-GlcNAcylation of H2B histone protein that correspond to changes in H3 trimethylation. Disruption of the cycle interfered with these periodic histone code alterations. Pharmacological inhibition of OGT with OSMI-1 disrupted the wake-sleep patterns of zebrafish without affecting expression of circadian rhythm-regulating genes. OSMI-1 inhibited the expression of c-fos, bdnf, and calm1, key genes associated with brain function and synaptic plasticity, and decreased the binding of O-GlcNAcylated H2B and OGT to promoter regions of these genes. The collective findings support the potential involvement of circadian cycling of the O-GlcNAc histone code in regulating synaptic plasticity and brain function. Overall, data from this study provide evidence that protein O-GlcNAcylation serves as a pivotal posttranslational mechanism integrating circadian signals and neuronal function to regulate rhythmic physiology., (© 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.)

A substantial number of patients develop cognitive dysfunction after contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), significantly contributing to long-coronavirus disease (COVID) morbidity. Despite the urgent and overwhelming clinical need, there are currently no proven interventions to treat post-COVID cognitive dysfunction (PCCD). Psychostimulants like methylphenidate may enhance both noradrenergic and dopaminergic pathways in mesolimbic and pre-frontal areas, thus improving memory and cognition. We present a case series of six patients who were treated at the Johns Hopkins Post-Acute COVID-19 Team (PACT) clinic for PCCD with methylphenidate 5 - 20 mg in the context of routine clinical care and followed for 4 to 8 weeks. Baseline and post-treatment outcomes included subjective cognitive dysfunction and objective performance on a battery devised to measure cognitive dysfunction in long-COVID patients. Three out of the six patients reported subjective improvement with methylphenidate, one patient described it as "notable" and another as "marked" improvement in memory and concentration. We also found significant pre-treatment subjective complaints of cognitive dysfunction; however, formal cognitive assessment scores were not severely impaired. A statistically significant difference in pre and post scores, favoring intervention, was found for the following cognitive assessments: Hopkins verbal learning test (HVLT) immediate recall, HVLT delayed recall and category-cued verbal fluency. The current series demonstrates promising neurocognitive effects of methylphenidate for long-COVID cognitive impairment, particularly in recall and verbal fluency domains., Competing Interests: None to declare., (Copyright 2024, Clark et al.)

Cell surface receptors play crucial roles in cellular responses to extracellular ligands, helping to modulate the functions of a cell based on information coming from outside the cell. Syndecan refers to a family of cell adhesion receptors that regulate both extracellular and cytosolic events. Alteration of syndecan expression disrupts regulatory mechanisms in a cell type-specific fashion, often leading to serious diseases, notably cancer. Given the multifaceted functions and distinct tissue distributions of syndecan, it will be important to unravel the gene-level intricacies of syndecan expression and thereby further understand its involvement in various carcinogenic processes. Although accumulating evidence indicates that the protein expression patterns of syndecan family members are significantly altered in cancer cells, the underlying gene-level mechanisms remain largely unknown. This review endeavors to explore syndecan gene expression levels across different cancer types by scrutinizing extensive cancer genome datasets using tools such as cBioPortal. Our analysis unveils that somatic mutations in SDC genes are rare occurrences, whereas copy number alterations are frequently observed across diverse cancers, particularly in SDC2 and SDC4 . Notably, amplifications of SDC2 and SDC4 correlate with heightened metastatic potential and dismal prognosis. This underscores the recurrent nature of SDC2 and SDC4 amplifications during carcinogenesis and sheds light on their role in promoting cancer activity through augmented protein expression. The identification of these amplifications not only enriches our understanding of carcinogenic mechanisms but also hints at the potential therapeutic avenue of targeting SDC2 and SDC4 to curb cancer cell proliferation and metastasis.

Background: Delirium is a common complication of older people in hospitals, rehabilitation and long-term facilities., Objective: To assess the worldwide use of validated delirium assessment tools and the presence of delirium management protocols., Design: Secondary analysis of a worldwide one-day point prevalence study on World Delirium Awareness Day, 15 March 2023., Setting: Cross-sectional online survey including hospitals, rehabilitation and long-term facilities., Methods: Participating clinicians reported data on delirium, the presence of protocols, delirium assessments, delirium-awareness interventions, non-pharmacological and pharmacological interventions, and ward/unit-specific barriers., Results: Data from 44 countries, 1664 wards/units and 36 048 patients were analysed. Validated delirium assessments were used in 66.7% (n = 1110) of wards/units, 18.6% (n = 310) used personal judgement or no assessment, and 10% (n = 166) used other assessment methods. A delirium management protocol was reported in 66.8% (n = 1094) of wards/units. The presence of protocols for delirium management varied across continents, ranging from 21.6% (on 21/97 wards/units) in Africa to 90.4% (235/260) in Australia, similar to the use of validated delirium assessments with 29.6% (29/98) in Africa to 93.5% (116/124) in North America. Wards/units with a delirium management protocol [n = 1094/1664, 66.8%] were more likely to use a validated delirium test than those without a protocol [odds ratio 6.97 (95% confidence interval 5.289-9.185)]. The presence of a delirium protocol increased the chances for valid delirium assessment and, likely, evidence-based interventions., Conclusion: Wards/units that reported the presence of delirium management protocols had a higher probability of using validated delirium assessments tools to assess for delirium., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Optimal reversal agent for direct oral anticoagulant (DOAC)-associated major bleeding has not been described. Before the approval of andexanet alfa (AA) in 2018, 4-factor prothrombin complex concentrate (4F-PCC) was recommended by major guidelines. Currently, AA is recommended as the first-line agent by most guidelines. With a paucity of literature comparing the 2 agents, there is clinical value in assessing hemostatic efficacy and safety of the 2 agents., Objective: This study aimed to evaluate hemostatic efficacy and safety of AA and 4F-PCC in all DOAC-associated major bleedings., Methods: A multicenter, retrospective chart review was performed of adult subjects who were admitted for a DOAC-associated major bleeding and received 4F-PCC from February 2018 to May 2019 or AA from May 2019 to September 2021. Some of the exclusion criteria included not receiving a DOAC, receiving multiple reversal agents during the same hospitalization, receiving reversal for any nonmajor bleeding indication, and not receiving the full dose of a reversal agent. The primary outcome was hemostatic efficacy 24 hours after the end of the reversal agent administration. Secondary outcomes included time to administration, hospital mortality, length of stay, need for surgery, and need for additional blood product. Safety outcome was incidence of thrombotic events., Results: There were 99 subjects included in the 4F-PCC group and 84 subjects in the AA group. Hemostatic efficacy was achieved in 69 subjects (69.7%) in the 4F-PCC group and 63 subjects (75%) in the AA group (P = 0.927). In-hospital mortality was seen in 20 subjects (20.2%) in the 4F-PCC group and 10 subjects (11.9%) in the AA group. Thrombotic events were seen in 7 subjects (7.1%) in the 4F-PCC group and 6 subjects (7.1%) in the AA group., Conclusions: There were no significant differences in hemostatic efficacy, in-hospital mortality, and number of thrombotic events between 4F-PCC and AA., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease and related dementias (ADRDs) and age-related hearing loss are the intersection of two major public health challenges. With age as the primary risk factor for both disease processes, the burden of ADRDs and age-related hearing loss is growing, and each field maintains significant barriers to broadscale identification and management that is affordable and accessible. With the disproportionate burden of ADRDs among racial and ethnic minority older adults and existing disparities within hearing care, both areas face challenges in achieving equitable access and outcomes across diverse populations. The publication of the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) trial in July 2023 marked a significant moment in the fields of brain and hearing health. The ACHIEVE trial was the first randomized controlled trial to examine whether providing hearing intervention, specifically provision of hearing aids, compared to an education control, would reduce cognitive changes over 3 years. The participants most at risk for cognitive decline, with lower education, lower income, more likely to identify as Black, and have more cardiovascular risk factors, were the participants who benefited most from the hearing intervention and are also the least likely to be represented in research and the least likely to obtain hearing care. With growing evidence of the interconnection between cognitive and sensory health, we have an opportunity to prioritize equity, from purposeful inclusion of diverse participants in trials to influencing the emerging market of over-the-counter hearing aids to supporting expanded models of hearing care that reach those who have traditionally gone unserved. No longer can hearing go unrecognized by clinicians, researchers, and advocates for brain health. At the same time, the fields of brain and hearing health must center equity if we are going to meet the needs of diverse older adults in a world in which hearing health matters., Competing Interests: Nieman reports receipt of grants from the National Institute on Aging and the National Institute on Deafness and Other Communication Disorders and serving as a volunteer board member for the non‐profit Hearing Loss Association of America and Access HEARS. Drs. Oh and Thorpe report receipt of grants from the National Institute on Aging. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: To increase skin permeability, various transdermal delivery techniques have been developed. However, due to the stratum corneum as a skin barrier, transdermal delivery remains limited., Aims: In this study, we evaluated efficacy and safety of arc-poration as a novel technique disrupting the stratum corneum., Results: Optical images and histological analysis using reconstituted human skin and porcine skin showed that the treatment of arc-poration created micropores with an average diameter of approximately 100 μm only to the depth of the stratum corneum, but not viable epidermis. In addition, the Franz diffusion cell experiment using reconstituted human skin showed a remarkable increase in permeability following pretreatment with arc-poration. Clinical results clearly demonstrated the enhancement of the skin-improving effect of cosmetics by pretreatment of arc-poration in terms of gloss, hydration, flakiness, texture, tone, tone evenness, and pigmentation of skin, without causing abnormal skin responses. The concentration of ozone and nitrogen oxides generated by arc-poration was below the permissible value for the human body., Conclusions: Arc-poration can increase skin permeability by creating stratum corneum-specific micropores, which can enhance the skin-improving effect of cosmetics without adverse responses., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Purpose of Review: Emergency departments (EDs) are facing an epidemic of overcrowding and ED boarding, particularly of older adults who often present with, or develop, delirium in the ED. Delirium is associated with increased complications, longer hospital length of stay, mortality, and costs to the healthcare system. However, we only have limited knowledge of how to successfully prevent and treat delirium in the ED in a pragmatic, sustainable, and cost-effective way. We present a narrative review of recent literature of delirium prevention and treatment programs in the ED. We aim to describe the components of successful delirium management strategies to be used by EDs in building delirium management programs., Recent Findings: We reviewed 10 studies (2005-2023) that report delirium interventions in the ED, and describe the different components of these interventions that have been studied. These interventions included: optimizing hemodynamics and oxygenation, treating pain, hydration and nutrition support, avoiding sedative hypnotics, antipsychotics and anticholinergics, promoting sleep, sensory stimulation, limiting the time spent in the ED, educating providers and staff, and developing multidisciplinary delirium protocols integrated into the electronic health record., Summary: Through our narrative review of the recent literature on delirium prevention and treatment programs in the ED, we have identified nine components of successful delirium prevention strategies in the ED. We also discuss three high priority areas for further research including identification of most effective components of delirium prevention strategies, conduct of additional high-quality trials in non-hip., Competing Interests: Conflict Interests The authors declare that they have no competing interests.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting from the complex interplay of genetic and environmental factors, meriting exploration using temporally dynamic biomarkers. DNA methylation-based algorithms have been trained to accurately estimate biological age, and deviation of predicted age from true age (epigenetic age acceleration) has been implicated in several inflammatory diseases, including asthma., Objective: We sought to determine the role of epigenetic and biological aging, telomere length, and epigenetically inferred abundance of 7 inflammatory biomarkers in AD., Methods: We performed DNA methylation-based analyses in a pediatric AD cohort (n = 24, mean ± standard deviation [SD] age 2.56 ± 0.28 years) and age-matched healthy subjects (n = 24, age 2.09 [0.15] years) derived from blood using 5 validated algorithms that assess epigenetic age (Horvath, Skin&Blood) and biological age (PhenoAge, GrimAge), telomere length (TelomereLength), and inflammatory biomarker levels., Results: Epigenetic and biological age, but not telomere length, were accelerated in AD patients for 4 algorithms: Horvath (+0.88 years; 95% confidence interval [CI], 0.33 to 1.4; P  = 2.3 × 10 -3 ), Skin&Blood (+0.95 years; 95% CI, 0.67 to 1.2; P  = 1.8 × 10 -8 ), PhenoAge (+8.2 years; 95% CI, 3.4 to 13.0; P  = 1.3 × 10 -3 ), and GrimAge (+1.8 years 95% CI, 0.22 to 3.3; P  = .026). Moreover, patients had increased levels of β 2 microglobulin (+47,584.4 ng/mL; P  = .029), plasminogen activation inhibitor 1 (+3,432.9 ng/mL; P  = 1.1 × 10 -5 ), and cystatin C (+31,691 ng/mL; P  = 4.0 × 10 -5 ), while levels of tissue inhibitor metalloproteinase 1 (-370.7 ng/mL; P  = 7.5 × 10 -4 ) were decreased compared to healthy subjects., Conclusion: DNA methylation changes associated with epigenetic and biological aging, and inflammatory proteins appear early in life in pediatric AD and may be relevant clinical biomarkers of pathophysiology., Competing Interests: This work was supported by funding from the 10.13039/100008582McGill University Faculty of Medicine & Health Sciences, the McGill University Health Centre Foundation, and the International Society of Atopic Dermatitis. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (© 2024 The Author(s).)

Background: Proinflammatory cytokines are implicated in the pathophysiology of postmenopausal bone loss. Clinical studies demonstrate that prunes prevent bone mineral density loss; however, the mechanism underlying this effect is unknown., Objective: We investigated the effect of prune supplementation on immune, inflammatory, and oxidative stress markers., Methods: A secondary analysis was conducted in the Prune Study, a single-center, parallel-arm, 12-mo randomized controlled trial of postmenopausal women (55-75 y old; n = 235 recruited; n = 183 completed) who were assigned to 1 of 3 groups: "no-prune" control, 50 g prune/d and 100 g prune/d groups. At baseline and after 12 mo of intervention, blood samples were collected to measure serum high-sensitivity C-reactive protein (hs-CRP), serum total antioxidant capacity (TAC), plasma 8-isoprostane, proinflammatory cytokines [interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1, and tumor necrosis factor (TNF)-α] concentrations in plasma and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) culture supernatants, and the percentage and activation of circulating monocytes, as secondary outcomes., Results: Prune supplementation did not alter hs-CRP, TAC, 8-isoprostane, and plasma cytokine concentrations. However, percent change from baseline in circulating activated monocytes was lower in the 100 g prune/d group compared with the control group (mean ± SD, -1.8% ± 4.0% in 100 g prune/d compared with 0.1% ± 2.9% in control; P < 0.01). Furthermore, in LPS-stimulated PBMC supernatants, the percent change from baseline in TNF-α secretion was lower in the 50 g prune/d group compared with the control group (-4.4% ± 43.0% in 50 g prune/d compared with 24.3% ± 70.7% in control; P < 0.01), and the percent change from baseline in IL-1β, IL-6, and IL-8 secretion was lower in the 100 g prune/d group compared with the control group (-8.9% ± 61.6%, -4.3% ± 75.3%, -14.3% ± 60.8% in 100 g prune/d compared with 46.9% ± 107.4%, 16.9% ± 70.6%, 39.8% ± 90.8% in control for IL-1β, IL-6, and IL-8, respectively; all P < 0.05)., Conclusions: Dietary supplementation with 50-100 g prunes for 12 mo reduced proinflammatory cytokine secretion from PBMCs and suppressed the circulating levels of activated monocytes in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT02822378., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Previous work showed that matrix metalloproteinase-7 (MMP-7) regulates colon cancer activities through an interaction with syndecan-2 (SDC-2) and SDC-2-derived peptide that disrupts this interaction and exhibits anticancer activity in colon cancer. Here, to identify potential anticancer agents, a library of 1,379 Food and Drug Administration (FDA)-approved drugs that interact with the MMP-7 prodomain were virtually screened by protein-ligand docking score analysis using the GalaxyDock3 program. Among five candidates selected based on their structures and total energy values for interacting with the MMP-7 prodomain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, everolimus, showed the highest binding affinity and the strongest ability to disrupt the interaction of the MMP-7 prodomain with the SDC-2 extracellular domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line did not affect the mRNA expression levels of MMP-7 and SDC-2 but reduced the adhesion of cells to MMP-7 prodomain-coated plates and the cell-surface localization of MMP-7. Thus, everolimus appears to inhibit the interaction between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their gelatin-degradation activity and anticancer activities, including colony formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, triggered less gelatin-degradation activity, suggesting that this inhibitory effect of everolimus was not due to inhibition of the mTOR pathway. Consistently, everolimus inhibited the colony-forming ability of mTOR-resistant HT29 cells. Together, these data suggest that, in addition to inhibiting mTOR signaling, everolimus exerts anticancer activity by interfering with the interaction of MMP-7 and SDC-2, and could be a useful therapeutic anticancer drug for colon cancer. NEW & NOTEWORTHY The utility of cancer therapeutics targeting the proteolytic activities of MMPs is limited because MMPs are widely distributed throughout the body and involved in many different aspects of cell functions. This work specifically targets the activation of MMP-7 through its interaction with syndecan-2. Notably, everolimus, a known mTOR inhibitor, blocked this interaction, demonstrating a novel role for everolimus in inhibiting mTOR signaling and impairing the interaction of MMP-7 with syndecan-2 in colon cancer.

The clinical observation and assessment of extra-ocular movements is common practice in assessing neurodegenerative disorders but remains observer-dependent. In the present study, we propose an algorithm that can automatically identify saccades, fixation, smooth pursuit, and blinks using a non-invasive eye tracker. Subsequently, response-to-stimuli-derived interpretable features were elicited that objectively and quantitatively assess patient behaviors. The cohort analysis encompasses persons with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), Parkinson's disease mimics (PDM), and controls (CTRL). Overall, results suggested that the AD/MCI and PD groups had significantly different saccade and pursuit characteristics compared to CTRL when the target moved faster or covered a larger visual angle during smooth pursuit. These two groups also displayed more omitted antisaccades and longer average antisaccade latency than CTRL. When reading a text passage silently, people with AD/MCI had more fixations. During visual exploration, people with PD demonstrated a more variable saccade duration than other groups. In the prosaccade task, the PD group showed a significantly smaller average hypometria gain and accuracy, with the most statistical significance and highest AUC scores of features studied. The minimum saccade gain was a PD-specific feature different from CTRL and PDM. These features, as oculographic biomarkers, can be potentially leveraged in distinguishing different types of NDs, yielding more objective and precise protocols to diagnose and monitor disease progression., Competing Interests: Declaration of competing interest None Declared, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Optimal reversal agent for direct oral anticoagulant (DOAC)-associated major bleeding has not been described. Before the approval of andexanet alfa (AA) in 2018, 4-factor prothrombin complex concentrate (4F-PCC) was recommended by major guidelines. Currently, AA is recommended as the first-line agent by most guidelines. With a paucity of literature comparing the 2 agents, there is clinical value in assessing hemostatic efficacy and safety of the 2 agents., Objective: This study aimed to evaluate hemostatic efficacy and safety of AA and 4F-PCC in all DOAC-associated major bleedings., Methods: A multicenter, retrospective chart review was performed of adult subjects who were admitted for a DOAC-associated major bleeding and received 4F-PCC from February 2018 to May 2019 or AA from May 2019 to September 2021. Some of the exclusion criteria included not receiving a DOAC, receiving multiple reversal agents during the same hospitalization, receiving reversal for any nonmajor bleeding indication, and not receiving the full dose of a reversal agent. The primary outcome was hemostatic efficacy 24 hours after the end of the reversal agent administration. Secondary outcomes included time to administration, hospital mortality, length of stay, need for surgery, and need for additional blood product. Safety outcome was incidence of thrombotic events., Results: There were 99 subjects included in the 4F-PCC group and 84 subjects in the AA group. Hemostatic efficacy was achieved in 69 subjects (69.7%) in the 4F-PCC group and 63 subjects (75%) in the AA group (P = 0.927). In-hospital mortality was seen in 20 subjects (20.2%) in the 4F-PCC group and 10 subjects (11.9%) in the AA group. Thrombotic events were seen in 7 subjects (7.1%) in the 4F-PCC group and 6 subjects (7.1%) in the AA group., Conclusions: There were no significant differences in hemostatic efficacy, in-hospital mortality, and number of thrombotic events between 4F-PCC and AA., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)