Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Risk Prediction of Post-Endoscopic Submucosal Dissection Coagulation Syndrome.

INTRODUCTION: Endoscopic submucosal dissection (ESD) has been popular worldwide to treat laterally spreading tumors and large polyps. Post-ESD coagulation syndrome (PECS) is more common than the two major ESD-related complications, perforation and bleeding. The aim of this study was to assess the prevalence of PECS, identify the risk factors for PECS, and create a risk prediction model for PECS. METHODS: Retrospective cross-sectional study analyzed a total of 986 patients who underwent colorectal ESD. Logistic regression models were used to assess risk factors with PECS. Each risk factor was scored and the 3-step risk stratification index of prediction model was assessed. RESULTS: The prevalence of PECS was 21.4% (95% confidence interval [CI]=18.9%-24.1%). The risk factors of PECS in the multivariate logistic regression were tumor size (+1 cm: odds ratio [OR], 1.29; 95% CI, 1.16 to 7.09), cecal lesion (OR, 1.96; 95% CI, 1.09 to 1.53), procedure time (+30 minutes: OR, 1.19; 95% CI, 1.02 to 1.39), and ESD with snaring (OR, 0.64; 95% CI, 0.43 to 0.95). Applying a simplified weighted scoring system based on adjusted OR increments of 1, the risk of PECS was 12.3% (95% CI, 0.3%-16.0%) for the low-risk group (score ≤ 4) and was 36.0% (95% CI=29.4%-43.2%) for the high-risk group (score ≥ 8). Overall discrimination (C-statistic=0.629; 95% CI=0.585-0.672) and calibration (p = 0.993) of the model were moderate to good. CONCLUSION: PECS occurs frequently and the prediction model can be helpful for effective treatment and prevention of PECS.

Prediction of Soluble-Solid Content in Citrus Fruit Using Visible-Near-Infrared Hyperspectral Imaging Based on Effective-Wavelength Selection Algorithm.

Citrus fruits were sorted based on external qualities, such as size, weight, and color, and internal qualities, such as soluble solid content (SSC), acidity, and firmness. Visible and near-infrared (VNIR) hyperspectral imaging techniques were used as rapid and nondestructive techniques for determining the internal quality of fruits. The applicability of the VNIR hyperspectral imaging technique for predicting the SSC in citrus fruits was evaluated in this study. A VNIR hyperspectral imaging system with a wavelength range of 400-1000 nm and 100 W light source was used to acquire hyperspectral images from citrus fruits in two orientations (i.e., stem and calyx ends). The SSC prediction model was developed using partial least-squares regression (PLSR). Spectrum preprocessing, effective wavelength selection through competitive adaptive reweighted sampling (CARS), and outlier detection were used to improve the model performance. The performance of each model was evaluated using the coefficient of determination (R2) and root mean square error (RMSE). In the present study, the PLSR model was developed using only a citrus cultivar. The SSC prediction CARS-PLSR model with outliers removed exhibited R2 and RMSE values of approximatively 0.75 and 0.56 °Brix, respectively. The results of this study are expected to be useful in similar fields such as agricultural and food post-harvest management, as well as in the development of an online system for determining the SSC of citrus fruits.

Baculovirus Vector-Based Varicella-Zoster Virus Vaccine as a Promising Alternative with Enhanced Safety and Therapeutic Functions.

Varicella-zoster virus (VZV) poses lifelong risks, causing varicella and herpes zoster (HZ, shingles). Currently, varicella and HZ vaccines are predominantly live attenuated vaccines or adjuvanted subunit vaccines utilizing VZV glycoprotein E (gE). Here, we propose our vaccine candidates involving a comparative analysis between recombinant baculoviral vector vaccines (AcHERV) and a live attenuated vaccine strain, vOka. AcHERV vaccine candidates were categorized into groups encoding gE only, VZV glycoprotein B (gB) only, or both gE and gB (gE-gB) as AcHERV-gE, AcHERV-gB, and AcHERV-gE-gB, respectively. Humoral immune responses were evaluated by analyzing total IgG, IgG1, IgG2a, and neutralizing antibodies. Cell-mediated immunity (CMI) responses were evaluated by enzyme-linked immunospot (ELISPOT) assay and Th1/Th2/Th17 cytokine profiling. In the mouse model, AcHERV-gE-gB elicited similar or higher total IgG, IgG2a, and neutralizing antibody levels than vOka and showed robust VZV-specific CMI responses. From the perspective of antigens encoded in vaccines and their relationship with CMI response, both AcHERV-gB and AcHERV-gE-gB demonstrated results equal to or superior to AcHERV-gE, encoding only gE. Taken together, these results suggest that AcHERV-gE-gB can be a novel candidate for alleviating risks of live attenuated vaccine-induced latency and effectively preventing varicella during early stages of life while providing strong CMI for effective resistance against HZ and therapeutic potential in later stages of life.

CRISPR/Cas9 targeting of passenger single nucleotide variants in haploinsufficient or essential genes expands cancer therapy prospects.

CRISPR/Cas9 technology has effectively targeted cancer-specific oncogenic hotspot mutations or insertion-deletions. However, their limited prevalence in tumors restricts their application. We propose a novel approach targeting passenger single nucleotide variants (SNVs) in haploinsufficient or essential genes to broaden therapeutic options. By disrupting haploinsufficient or essential genes through the cleavage of DNA in the SNV region using CRISPR/Cas9, we achieved the selective elimination of cancer cells without affecting normal cells. We found that, on average, 44.8% of solid cancer patients are eligible for our approach, a substantial increase compared to the 14.4% of patients with CRISPR/Cas9-applicable oncogenic hotspot mutations. Through in vitro and in vivo experiments, we validated our strategy by targeting a passenger mutation in the essential ribosomal gene RRP9 and haploinsufficient gene SMG6. This demonstrates the potential of our strategy to selectively eliminate cancer cells and expand therapeutic opportunities.

Perspective: Promoting Healthy Aging through Nutrition: A Research Centers Collaborative Network Workshop Report.

Within 20 y, the number of adults in the United States over the age of 65 y is expected to more than double and the number over age 85 y is expected to more than triple. The risk for most chronic diseases and disabilities increases with age, so this demographic shift carries significant implications for the individual, health care providers, and population health. Strategies that delay or prevent the onset of age-related diseases are becoming increasingly important. Although considerable progress has been made in understanding the contribution of nutrition to healthy aging, it has become increasingly apparent that much remains to be learned, especially because the aging process is highly variable. Most federal nutrition programs and nutrition research studies define all adults over age 65 y as "older" and do not account for physiological and metabolic changes that occur throughout older adulthood that influence nutritional needs. Moreover, the older adult population is becoming more racially and ethnically diverse, so cultural preferences and other social determinants of health need to be considered. The Research Centers Collaborative Network sponsored a 1.5-d multidisciplinary workshop that included sessions on dietary patterns in health and disease, timing and targeting interventions, and health disparities and the social context of diet and food choice. The agenda and presentations can be found at https://www.rccn-aging.org/nutrition-2023-rccn-workshop. Here we summarize the workshop's themes and discussions and highlight research gaps that if filled will considerably advance our understanding of the role of nutrition in healthy aging.

Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

Deep learning-based, fully automated, pediatric brain segmentation.

The purpose of this study was to demonstrate the performance of a fully automated, deep learning-based brain segmentation (DLS) method in healthy controls and in patients with neurodevelopmental disorders, SCN1A mutation, under eleven. The whole, cortical, and subcortical volumes of previously enrolled 21 participants, under 11 years of age, with a SCN1A mutation, and 42 healthy controls, were obtained using a DLS method, and compared to volumes measured by Freesurfer with manual correction. Additionally, the volumes which were calculated with the DLS method between the patients and the control group. The volumes of total brain gray and white matter using DLS method were consistent with that volume which were measured by Freesurfer with manual correction in healthy controls. Among 68 cortical parcellated volume analysis, the volumes of only 7 areas measured by DLS methods were significantly different from that measured by Freesurfer with manual correction, and the differences decreased with increasing age in the subgroup analysis. The subcortical volume measured by the DLS method was relatively smaller than that of the Freesurfer volume analysis. Further, the DLS method could perfectly detect the reduced volume identified by the Freesurfer software and manual correction in patients with SCN1A mutations, compared with healthy controls. In a pediatric population, this new, fully automated DLS method is compatible with the classic, volumetric analysis with Freesurfer software and manual correction, and it can also well detect brain morphological changes in children with a neurodevelopmental disorder.

Performance Improvement of Partial Least Squares Regression Soluble Solid Content Prediction Model Based on Adjusting Distance between Light Source and Spectral Sensor according to Apple Size.

Apples are widely cultivated in the Republic of Korea and are preferred by consumers for their sweetness. Soluble solid content (SSC) is measured non-destructively using near-infrared (NIR) spectroscopy; however, the SSC measurement error increases with the change in apple size since the distance between the light source and the near-infrared sensor is fixed. In this study, spectral characteristics caused by the differences in apple size were investigated. An optimal SSC prediction model applying partial least squares regression (PLSR) to three measurement conditions based on apple size was developed. The three optimal measurement conditions under which the Vis/NIR spectrum is less affected by six apple size levels (Levels I-VI) were selected. The distance from the apple center to the light source and that to the sensor were 125 and 75 mm (Distance 1), 123 and 75 mm (Distance 2), and 135 and 80 mm (Distance 3). The PLSR model applying multiplicative scatter correction pretreatment under Distance 3 measurement conditions showed the best performance for Level IV-sized apples (Rpre2 = 0.91, RMSEP = 0.508 °Brix). This study shows the possibility of improving the SSC prediction performance of apples by adjusting the distance between the light source and the NIR sensor according to fruit size.

Validation of a Novel Allergy-Specific Domain for the 22-Item Sino-Nasal Outcomes Test.

OBJECTIVES: To develop and assess the validity of a novel allergy-specific domain for the 22-item sino-nasal outcomes test (SNOT-22), to provide a new tool that efficiently quantifies the impact of allergic rhinitis (AR) concurrent with chronic rhinosinusitis. STUDY DESIGN: Prospective validation study. SETTING: Tertiary care hospital and community-based clinic. METHODS: Proposed items were developed based on clinician and patient input, and further assessed via factor analysis and for internal consistency (n = 1987). Items were then additionally assessed for convergent and discriminant validity (n = 415), applying data from concurrent completions of the Nasal Obstruction and Septoplasty Effectiveness Scale (NOSE), Mini-Rhinoconjunctivitis Quality-of-Life Questionnaire (MiniRQLQ), and validated global health assessments. Assessments of intra-rater reliability, responsiveness to change, and qualitative input were also performed. RESULTS: Factor analysis demonstrated that proposed allergy items mapped to a single domain. Items were internally consistent (Cronbach α: 0.80 within domain, 0.91 within all SNOT). In assessments of convergent validity, domain scores were associated with MiniRQLQ (Spearman's ρ: 0.46, 95% confidence interval [CI]: 0.30-0.59) and NOSE scores (0.36, 95% CI: 0.27-0.44). The novel items also discriminated among clinical states: a 1-point increase in domain score was associated with an 8.32 (95% CI: 5.43-12.75) increase in the odds of prompting a visit for allergy-related symptoms and a 1.52 (95% CI: 1.13-2.05) increase in the odds of positive allergy testing. Intra-rater reliability was substantial (Cohen's κ: 0.8, 95% CI: 0.8-0.9), and responsiveness to change was demonstrated (mean difference: -0.6, 95% CI: -0.8 to -0.4). CONCLUSIONS: This novel domain is a valid, efficient measure of AR alongside rhinosinusitis.

Early Weight-Bearing After Fibula Free Flap Surgery.

Importance: Despite the widespread use of fibula free flap (FFF) surgery for head and neck reconstruction, there are no studies assessing if early weight-bearing (EWB) affects postoperative recovery, and the timing of weight-bearing initiation following FFF surgery varies considerably across institutions. Therefore, it is important to understand the effect of EWB in these patients and whether it could improve postoperative recovery. Objective: To assess the association of EWB after FFF surgery with donor-site complications, length of stay, and discharge to home status. Design, Setting, and Participants: This retrospective cohort study took place at Massachusetts Eye and Ear, a single tertiary care institution in Boston, Massachusetts. A total of 152 patients who received head and neck reconstruction with a fibula osteocutaneous free flap between January 11, 2010, and August 11, 2022, were included. Exposure: EWB on postoperative day 1 vs non-EWB on postoperative day 2 or later. Main Outcomes and Measures: Patient characteristics, including demographic characteristics and comorbidities, surgical characteristics, donor-site complications, length of stay, and discharge disposition, were recorded. Descriptive statistics and multivariate logistic regressions were used to compute effect sizes and 95% CIs to compare postoperative outcomes in EWB and non-EWB groups. Results: A total of 152 patients (median [IQR] age, 63 [55-70] years; 89 [58.6%] male) were included. The median (IQR) time to postoperative weight-bearing was 3 (1-5) days. Among all patients, 14 (9.2%) had donor-site complications. EWB on postoperative day 1 was associated with shorter length of stay (adjusted odds ratio [AOR], 0.10; 95% CI, 0.02-0.60), increased rate of discharge to home (AOR, 7.43; 95% CI, 2.23-24.80), and decreased donor-site complications (AOR, 0.11; 95% CI, 0.01-0.94). Conversely, weight-bearing 3 or more days postoperatively was associated with an increased risk of pneumonia (AOR, 6.82; 95% CI, 1.33-34.99). Conclusions and Relevance: In this cohort study, EWB after FFF surgery was associated with shorter length of stay, increased rate of discharge to home, and decreased donor-site complications. These findings support the role of early mobilization to optimize postoperative recovery after FFF surgery.

Outcomes of Primary Esophagectomy and Esophagectomy after Endoscopic Submucosal Dissection for Superficial Esophageal Squamous Cell Carcinoma: A Propensity-Score-Matched Analysis.

Even though the conventional treatment for T1 esophageal cancer is surgery, ESD is becoming the primary treatment. Currently, it is unknown whether secondary esophagectomy after endoscopic submucosal dissection (ESD) is comparable to primary esophagectomy when considering outcomes in patients with T1 esophageal cancer. We compared short- and long-term clinical outcomes between the two groups. Primary surgery (esophagectomy) was performed in 191 patients between 2003 and 2014, and 62 patients underwent secondary surgery (esophagectomy) after ESD for T1 esophageal cancer between 2007 and 2019. Propensity matching was performed for age, sex, Charlson Comorbidity Index (CCI), location, pathology, degree of differentiation, tumor size, and invasion depth. Lymph node metastasis (LNM), overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), and post-operative complications were compared between groups. Sixty-eight patients were included after propensity score matching; LNM, OS, DSS, and RFS were comparable between the two groups. Comparing primary and secondary surgery, the respective LNM rates were 23.5% and 26.5%, 6-year OS 78.0% and 89.7%, p = 0.15; DSS were 80.4% and 96.8%, p = 0.057; and RFS were 80.8% and 89.7%, p = 0.069. Comparing the adverse events between the two groups, there was no significant difference in the overall adverse events. However, more early complications were observed in the primary surgery group than in the secondary surgery group (50% vs. 20.6%, p = 0.021). Secondary surgery did not increase the risk of LNM. The long-term outcomes were comparable. Therefore, attempts to perform upfront ESD for superficial esophageal squamous cell cancers are justified.

IDF-11774 Induces Cell Cycle Arrest and Apoptosis by Inhibiting HIF-1α in Gastric Cancer.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a regulatory factor of intracellular oxygen supersession. The expression or increased activity of HIF-1α is closely related to various human cancers. Previously, IDF-11774 was demonstrated to inhibit HSP70 chaperone activity and suppress the accumulation of HIF-1α. In this study, we aimed to determine the effects of IDF-11774 on gastric cancer cell lines. Treatment with IDF-11774 was found to markedly decrease the proliferation, migration, and invasion of the gastric cancer cell lines. Furthermore, the phosphorylation levels of extracellular signal-regulated kinase 1/2, p38, and Jun N-terminal kinase in the mitogen-activated protein kinase signaling pathways were markedly increased in a dose-dependent manner, ultimately promoting apoptosis via the induction of cell cycle arrest. Our findings indicate that HIF-1α inhibitors are potent drugs for the treatment of gastric cancer.

Attenuated Chimeric GI/GIII Vaccine Candidate against Japanese Encephalitis Virus.

Japanese encephalitis (JE) is a very severe disease characterized by high fatality rates and the development of permanent behavioral, psychiatric, and neurological sequelae among survivors. Japanese encephalitis virus (JEV), a flavivirus, is responsible for JE. In Asia, Genotype I (GI) has emerged as the dominant strain, replacing Genotype III (GIII). However, no clinically approved drug is available to treat JEV infection, and currently available commercial vaccines derived from JEV GIII strains provide only partial protection against GI. Utilizing a reverse genetics system, this study attempted to produce a novel chimeric JEV strain with high efficacy against JEV GI. Accordingly, a GI/GIII intertypic recombinant strain, namely SA14-GI env, was generated by substituting the E region of the GIII SA14-14-2 strain with that of the GI strain, K05GS. The neurovirulence of the mutant virus was significantly reduced in mice. Analysis of the immunogenicity of the chimeric virus revealed that it induced neutralizing antibodies against JEV GI in mice, and the protective efficacy of SA14-GI env was higher than that of SA14-14-2. These findings suggest that SA14-GI env may be a safe and effective live-attenuated vaccine candidate against JEV GI.

Cognitive function, self-management, and outcomes among liver transplant recipients: LivCog, a multicenter, prospective study.

Liver transplantation is a life-saving option for decompensated cirrhosis. Liver transplant recipients require advanced self-management skills, intact cognitive skills, and care partner support to improve long-term outcomes. Gaps remain in understanding post-liver transplant cognitive and health trajectories, and patient factors such as self-management skills, care partner support, and sleep. Our aims are to (1) assess pre-liver transplant to post-liver transplant cognitive trajectories and identify risk factors for persistent cognitive impairment; (2) evaluate associations between cognitive function and self-management skills, health behaviors, functional health status, and post-transplant outcomes; and (3) investigate potential mediators and moderators of associations between cognitive function and post-liver transplant outcomes. LivCog is a longitudinal, prospective observational study that will enroll 450 adult liver transplant recipients and their caregivers/care partners. The duration of the study is 5 years with 24 additional months of patient follow-up. Data will be collected from participants at 1, 3, 12, and 24 months post-transplant. Limited pre-liver transplant data will also be collected from waitlisted candidates. Data collection methods include interviews, surveys, cognitive assessments, and actigraphy/sleep diary measures. Patient measurements include sociodemographic characteristics, pretransplant health status, cognitive function, physical function, perioperative measures, medical history, transplant history, self-management skills, patient-reported outcomes, health behaviors, and clinical outcomes. Caregiver measures assess sociodemographic variables, health literacy, health care navigation skills, self-efficacy, care partner preparedness, nature and intensity of care, care partner burden, and community participation. By elucidating various health trajectories from pre-liver transplant to 2 years post-liver transplant, LivCog will be able to better characterize recipients at higher risk of cognitive impairment and compromised self-management. Findings will inform interventions targeting health behaviors, self-management, and caregiver supports to optimize outcomes.

Weight loss from diagnosis of Crohn's disease to one year post-diagnosis results in earlier surgery.

Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD). The aim of this study was to explore the impact of weight loss from diagnosis of CD to one-year post-diagnosis on disease prognosis in terms of surgery. Patients who were diagnosed with CD at Samsung Medical Center between 1995 to 2020 were included in this study. The study defined the "group with weight loss" as patients with weight loss in one year after diagnosis and the "group without body weight loss" as patients without weight loss in one year after diagnosis. Their data such as demographics, laboratory findings, and medical interventions were collected retrospectively. The primary outcome was confirmation of the difference in the incidence of surgery associated with CD between the group with weight loss and the group without body weight loss. We further analyzed factors associated with surgery outcomes. A total of 165 patients were analyzed in this study. Forty-one patients (24.8%) had body weight loss whereas 124 patients (75.2%) had no body weight loss. Body change at one year showed no significant association with direct surgical incidence. However, the patients with weight loss tended to undergo surgery earlier than patients without body weight loss. Among factors associated with outcomes of Crohn's surgery, the albumin was the only significant factor. Patients with weight loss had no statistically significant increase in the risk of surgery than patients without weight loss, although they tended to undergo surgery earlier than patients without body weight loss. A prospective study is needed to determine serial body weight changes during follow-up for patients with CD.

Primary care detection of cognitive impairment leveraging health and consumer technologies in underserved US communities: protocol for a pragmatic randomised controlled trial of the MyCog paradigm.

INTRODUCTION: Early identification of cognitive impairment (CI), including Alzheimer's disease and related dementias (ADRD), is a top public health priority. Yet, CI/ADRD is often undetected and underdiagnosed within primary care settings, and in health disparate populations. The MyCog paradigm is an iPad-based, self-administered, validated cognitive assessment based on the National Institutes of Health (NIH) Toolbox Cognition Battery and coupled with clinician decision-support tools that is specifically tailored for CI/ADRD detection within diverse, primary care settings. METHODS AND ANALYSIS: We will conduct a two-arm, primary care practice-randomised (N=24 practices; 45 257 active patients at the proposed practices), pragmatic trial among geographically diverse Oak Street Health sites to test the effectiveness of the MyCog paradigm to improve early detection CI/ADRD among low socioeconomic, black and Hispanic older adults compared with usual care. Participating practices randomised to the intervention arm will impart the MyCog paradigm as a new standard of care over a 3-year implementation period; as the cognitive component for Annual Wellness Visits and for any patient/informant-reported or healthcare provider-suspected cognitive concern. Rates of detected (cognitive test suggesting impairment) and/or diagnosed (relevant International Classification of Diseases-9/10 [ICD-9/10] code) cognitive deficits, impairments or dementias including ADRD will be our primary outcome of study compared between arms. Secondary outcomes will include ADRD severity (ie, mild or later stage), rates of cognitive-related referrals and rates of family member or caregiver involvement in ADRD care planning. We will use generalised linear mixed models to account for clustered study design. Secondary models will adjust for subject, clinic or visit-specific characteristics. We will use mixed-methods approaches to examine fidelity and cost-effectiveness of the MyCog paradigm. ETHICS AND DISSEMINATION: The Institutional Review Board at Advarra has approved the study protocol (Pro00064339). Results will be published in peer-reviewed journals and summaries will be provided to the funders of the study. TRIAL REGISTRATION NUMBER: NCT05607732.

Elucidating anti-aging and antioxidant activity of Hydnocarpus anthelmintica on skin aging and cosmeceutical potentials: in silico and in vitro study.

INTRODUCTION: Hydnocarpus anthelmintica (HA) has been traditionally used for treating leprosy and is known for its antioxidant and anti-inflammatory activities. The aim of this study was to investigate the active compounds and targets of HA extracts, involved in oxidative stress and skin aging. The active compounds and targets of HA extracts were identified using network pharmacology. METHOD: The pathway study was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. HA semen was measured for its in-vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and anti-aging activities using collagenase, elastase, and tyrosinase assays. A total of 21 intersecting core targets were identified from 8 compounds, 51 action targets, and 1810 skin aging and oxidative stress-associated target genes. RESULT: A compound-target network was constructed, and 3 compounds (luteolin, beta-carotene and genkwanin), and 4 hub genes (TP53, HSP90AA1, JUN, and MAPK1) were identified. The KEGG pathway study revealed that the compounds were correlated with PI3K-Akt, p53, HIF-1, and MAPK signaling. CONCLUSION: The results of in-vitro experiments showed the effect of HA extract on oxidative stress reduction and collagenase inhibition. We discovered two main active compounds, luteolin and ß-carotene, that may be involved in p53 and MAPK signaling, and showed HA extract activity against oxidative stress and collagenase.

Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy.

Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN. Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo. Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio. Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.