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BackgroundGout is a form of chronic arthritis caused by elevated serum uric acid (SUA) and culminates in painful gout attacks. Although effective uric acid-lowering therapies exist, adherence is low. This is partly due to the lack of support for patients to self-manage their disease. Mobile health apps have been used in the self-management of chronic conditions. However, not all are developed with patients, limiting their effectiveness. ObjectiveThe objective of our study was to collect feedback from gout patients to design an effective gout self-management app. MethodsTwo descriptive qualitative studies were conducted. In Study 1, researchers developed a short educational video and written materials about gout management, designed to be embedded into an app; 6 interviews and 1 focus group were held with gout patients to gather feedback on these materials. Usability testing in Study 2 involved additional gout patients using a pilot version of Healthy.me Gout, a gout self-management app, for 2 weeks. Following the trial, patients participated in an interview about their experiences using the app. ResultsPatients viewed the gout educational material positively, appreciating the combined use of video, text, and images. Patients were receptive to using a mobile app to self-manage their gout. Feedback about Healthy.me Gout was generally positive with patients reporting that the tracking and diary features were most useful. Patients also provided suggestions for improving the app and educational materials. ConclusionsThese studies involved patients in the development of a gout self-management app. Patients provided insight to improve the app’s presentation and usability and general lessons on useful features for chronic disease apps. Gout patients enjoyed tracking their SUA concentrations and gout attack triggers. These capabilities can be translated into self-management apps for chronic diseases that require monitoring of pathological values, medication adherence, or symptoms. Future health app design should integrate patient input and be developed iteratively to address concerns identified by patients.

Dilation of perivascular spaces (PVS) in the brain may indicate poor fluid drainage due to the accumulation of perivascular cell debris, waste, and proteins, including amyloid-beta (Aβ). No prior study has assessed whether plasma Aβ levels are related to PVS in older adults without dementia. Independently living older adults (N = 56, mean age = 68.2 years; Standard deviation (SD) = 6.5; 30.4% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. PVS were qualitatively scored and dichotomized to low PVS burden (scores 0-1,) or high PVS burden (score>1). Plasma was assayed using a Quanterix Simoa Kit to quantify Aβ42 and Aβ40 levels. A significant difference was observed in plasma Aβ42/Aβ40 ratio between low and high PVS burden, controlling for age (F[1, 53] = 5.59, p = 0.022, η2 = 0.10), with lower Aβ42/Aβ40 ratio in the high PVS burden group. Dilation of PVS is associated with a lower plasma Aβ42/Aβ40 ratio, which may indicate higher cortical amyloid deposition. Future longitudinal studies examining PVS changes, and the pathogenesis of AD are warranted.

BackgroundElevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury.MethodsThe present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.6 [SD 8.7] years) without a history of dementia or stroke. Short-term BP variability was determined from BP measurements collected continuously during a 5-minute resting period followed by cerebrovascular reactivity during 5-minute hypocapnia and hypercapnia challenge induced by visually guided breathing conditions. Cerebrovascular reactivity was quantified as percent change in cerebral perfusion by pseudo-continuous arterial spin labeling (pCASL)-MRI per unit change in end-tidal CO2.ResultsElevated systolic BP variability was related to lower whole brain cerebrovascular reactivity during hypocapnia (ß = -0.43 [95% CI -0.73, -0.12]; P = 0.008; adjusted R2 =.11) and hypercapnia (ß = -0.42 [95% CI -0.77, -0.06]; P = 0.02; adjusted R2 = 0.19).ConclusionsFindings add to prior work linking BP variability and cerebrovascular disease burden and suggest BP variability may also be related to prodromal markers of cerebrovascular dysfunction and disease, with potential therapeutic implications.

ObjectivesWe describe the perceptions and experiences of anti-Asian racism and violence and depression severity prior to and during the COVID-19 pandemic among a sample of Asian American (AA) adolescents and young adults.MethodsWe used data from the Young Asian American Health Survey (YAAHS), an online-recruited sample of AA adolescents (ages 13-17) and young adults (ages 18-29 years) conducted during May 2021 to March 2022. We presented descriptive statistics examining the univariate distribution and bivariate relationships of depression severity, sociodemographic characteristics, and experiences and perceptions of anti-Asian violence.ResultsOur sample (n = 176) comprised AA adolescents and young adults from 17 Asian ethnicities. A quarter said that the frequency and/or severity of their personal experiences of anti-Asian harassment had increased since the pandemic started. 76% indicated feeling less safe now than before the pandemic. Two-thirds reported that their depressive symptoms have increased since the pandemic started. Participants who reported feeling less safe now than before the pandemic were more likely to report increased personal experiences with anti-Asian harassment and increased depression severity since the pandemic started than those who reported feeling as safe or safer before the pandemic (p < 0.01 for both).DiscussionFindings illustrate AA adolescent and young adults are experiencing multiple health and social crises stemming from increased anti-Asian racism during the COVID-19 pandemic. We urge policymakers to strengthen data systems that connect racial discrimination and mental health and to institute prevention measures and anti-racist mental health services that are age- and culturally-appropriate for AA adolescent and young adults.

Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.9 [8.2 SD]), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aβ1-42 (standardized ß =  - 0.36 [95% CI - 0.61, - 0.12]; p = 0.005; adjusted R2 = 0.28) and Aβ1-42: Aβ1-40 ratio (ß =  - 0.49 [95% CI - 0.71, - 0.22]; p

Frequent injections of anti-vascular endothelial growth factor (anti-VEGF) agents are a clinical burden for patients with neovascular age-related macular degeneration (AMD). Genomic disruption of VEGF-A using adeno-associated viral (AAV) delivery of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 has the potential to permanently suppress aberrant angiogenesis, but the factors that determine the optimal efficacy are unknown. Here, we investigate two widely used Cas9 endonucleases, SpCas9 and SaCas9, and evaluate the relative contribution of AAV-delivery efficiency and genome-editing rates in vivo to determine the mechanisms that drive successful CRISPR-based suppression of VEGF-A, using a mouse model of laser-induced choroidal neovascularization (CNV). We found that SpCas9 demonstrated higher genome-editing rates, greater VEGF reduction, and more effective CNV suppression than SaCas9, despite similar AAV transduction efficiency between a dual-vector approach for SpCas9 and single-vector system for SaCas9 to deliver the Cas9 orthologs and single guide RNAs (gRNAs). Our results suggest that successful VEGF knockdown using AAV-mediated CRISPR systems may be determined more by the efficiency of genome editing rather than viral transduction and that SpCas9 may be more effective than SaCas9 as a potential therapeutic strategy for CRISPR-based treatment of CNV in neovascular AMD.

Online homework systems have been shown to help student achievement in chemistry courses. This study sought to compare the levels of knowledge retention in students over the course of a semester, using two different types of homework systems--the adaptive-responsive system and the traditional-responsive system. Two sections of a first semester general chemistry course were investigated, with one section using the adaptive-responsive system and the other using the traditional-responsive system. Students' grades on cumulative exams were compared across both sections, and it was found that students using the adaptive-responsive system scored significantly higher on the exams and retained significantly more information than the students in the other section. The results of this study should help inform the choices educators make regarding the homework system they choose to use, or even which parts of the different systems they choose to use or not to use based on the outcomes they would like for their student population.

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes persistent infection in the host by encoding a vast network of proteins that aid immune evasion. One of these targeted innate immunity pathways is the cGAS-STING pathway, which inhibits the reactivation of KSHV from latency. Previously, we identified multiple cGAS/STING inhibitors encoded by KSHV, suggesting that the counteractions of this pathway by viral proteins are critical for maintaining a successful KSHV life cycle. However, the detailed mechanisms of how these viral proteins block innate immunity and facilitate KSHV lytic replication remain largely unknown. In this study, we report that ORF48, a previously identified negative regulator of the cGAS/STING pathway, is required for optimal KSHV lytic replication. We used both siRNA and deletion-based systems to evaluate the importance of intact ORF48 in the KSHV lytic cycle. In both systems, loss of ORF48 resulted in defects in lytic gene transcription, lytic protein expression, viral genome replication and infectious virion production. ORF48 genome deletion caused more robust and global repression of the KSHV transcriptome, possibly due to the disruption of RTA promoter activity. Mechanistically, overexpressed ORF48 was found to colocalize and interact with endogenous STING in HEK293 cells. Endogenous ORF48 and STING interactions were also detected in reactivated iSLK.219 cells. Compared with the control cell line, HUVEC cells stably expressing ORF48 exhibited repressed STING-dependent innate immune signaling upon ISD or diABZI treatment. However, the loss of ORF48 in our iSLK-based lytic system failed to induce IFNβ production, suggesting a redundant role of ORF48 on STING signaling during the KSHV lytic phase. Thus, ORF48 is required for optimal KSHV lytic replication through additional mechanisms that need to be further explored. Author summary: Kaposi's sarcoma-associated herpesvirus (KSHV) causes persistent infection in a host that leads to two deadly cancers, Kaposi sarcoma and primary effusion lymphoma, especially in immunocompromised people. Unfortunately, there is no vaccine or viral-specific treatment for KSHV-related diseases, due to our limited knowledge of detailed immune evasion strategies by KSHV. KSHV blocks multiple immune pathways to maintain its lifelong infection, one of which is the DNA-sensing cGAS-STING pathway. Here, we reported that ORF48, a KSHV-encoded STING inhibitor is required for optimal KSHV lytic reactivation and viral production. A successful KSHV infection requires both intact ORF48 DNA and mRNA at different stages of its lytic life cycle. Further study reveals that ORF48 binds to STING and blocks STING-dependent innate immunity, and additional mechanisms may contribute to its role in lytic replication. Our findings provide insight into viral immune evasion strategies, which would contribute to a better understanding of all viral diseases. [ABSTRACT FROM AUTHOR]

Aim: Cardiovascular diseases are the leading cause of death globally. Ensuring ongoing use of medicines—medication persistence—is crucial, yet no prior studies have examined this in residential aged care facilities (RACFs). We aimed to identify long‐term trajectories of persistence with cardiovascular medicines and determine predictors of persistence trajectories. Method: A longitudinal cohort study of 2837 newly admitted permanent residents from 30 RACFs in New South Wales, Australia. We monitored weekly exposure to six cardiovascular medicine classes—lipid modifiers, angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs), beta‐blockers, diuretics, calcium channel blockers (CCB), and cardiac therapy—over 3 years. Group‐based trajectory modeling was employed to determine persistence trajectories for each class. Results: At baseline, 76.6% (n = 2172) received at least one cardiovascular medicine with 41.2% receiving lipid modifiers, 31.4% ACEI/ARBs, 30.2% beta‐blockers, 24.4% diuretics, 18.7% CCBs, and 14.8% cardiac therapy. The model identified two persistence trajectories for CCBs and three trajectories for all other classes. Sustained high persistence rates ranged from 68.4% (ACEI/ARBs) to 79.8% (beta‐blockers) while early decline in persistence and subsequent discontinuation rates ranged from 7.6% (cardiac therapy) to 25.3% (CCBs). Logistic regressions identified 11 predictors of a declining persistence across the six medicine classes. Conclusion: Our study revealed varied patterns of cardiovascular medicine use in RACFs, with 2–3 distinctive medicine use trajectories across different classes, each exhibiting a unique clinical profile, and up to a quarter of residents discontinuing a medicine class. Future studies should explore the underlying reasons and appropriateness of nonpersistence to aid in identifying areas for improvement. [ABSTRACT FROM AUTHOR]