INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC): An NIA and VA-sponsored initiative to increase veteran participation in aging and dementia research.

INTRODUCTION: Older military veterans often present with unique and complex risk factors for Alzheimer's disease (AD) and related dementias. Increasing veteran participation in research studies offers one avenue to advance the field and improve health outcomes. METHODS: To this end, the National Institute on Aging (NIA) and Department of Veterans Affairs (VA) partnered to build infrastructure, improve collaboration, and intensify targeted recruitment of veterans. This initiative, INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC), provided funding for five sites and cross-site organizing structure. Diverse and innovative recruitment strategies were used. RESULTS: Across five sites, 172 veterans entered registries, and 99 were enrolled into ADRC studies. Of the enrolled, 39 were veterans from historically underrepresented racial and ethnic groups. CONCLUSIONS: This initiative laid the groundwork to establish sustainable relationships between the VA and ADRCs. The partnership between both federal agencies demonstrates how mutual interests can accelerate progress. In turn, efforts can help our aging veterans.

Lessons From the Coronavirus Disease Experience: Research Participant and Staff Satisfaction With Remote Cognitive Evaluations.

OBJECTIVE: In New York City in 2020 the pandemic shut down in-person research. Icahn School of Medicine's Alzheimer's Disease Research Center transitioned longitudinal evaluations from in-person to telephone to enhance equity of access. We assessed diverse research participants' and clinical research coordinators' (CRC) satisfaction with remote evaluation and examined sociodemographic, cognitive, and behavioral factors that might impact satisfaction. METHODS: Data collected: 241 participants with Clinical Dementia Rating (CDR) = 0/0.5 (3/2020 to 6/2021). A Telehealth Satisfaction Questionnaire for CRCs and participants was administered at the end of remote evaluations. We compared Telehealth Satisfaction Questionnaire items by CDR and Geriatric Depression Scale. RESULTS: Participants' mean age was 78.4, 61.4% were females, 16.2% were Hispanic, 17.1% Asian, 15.8% were non-Hispanic black, and 72.6% CDR = 0. Participant satisfaction was high [14.1 ± 1.4 (out of 15)] but was lower among those with depression. CRC satisfaction was high [16.9 ± 1.8 (out of 18)] but was lower concerning the ability to explain the test battery and interact with participants with CDR = 0.5. CONCLUSION: Telephone research assessments provide flexibility in a hybrid model. They offer equitable access to research participation for those who do not use computer technology and may promote the retention of diverse elderly research participants.

Liberation of host heme by Clostridioides difficile-mediated damage enhances Enterococcus faecalis fitness during infection.

IMPORTANCE: Clostridioides difficile and Enterococcus faecalis are two pathogens of great public health importance. Both bacteria colonize the human gastrointestinal tract where they are known to interact in ways that worsen disease outcomes. We show that the damage associated with C. difficile infection (CDI) releases nutrients that benefit E. faecalis. One particular nutrient, heme, allows E. faecalis to use oxygen to generate energy and grow better in the gut. Understanding the mechanisms of these interspecies interactions could inform therapeutic strategies for CDI.

Carbonic Anhydrase Inhibition as a Target for Antibiotic Synergy in Enterococci.

Enterococcus faecalis is a hospital-associated opportunistic pathogen that can cause infections with high mortality, such as infective endocarditis. With an increasing occurrence of multidrug-resistant enterococci, there is a need for alternative strategies to treat enterococcal infections. We isolated a gentamicin-hypersusceptible E. faecalis strain from a patient with infective endocarditis that carried a mutation in the alpha-carbonic anhydrase (α-CA) and investigated how disruption of α-CA sensitized E. faecalis to killing with gentamicin. The gentamicin-hypersusceptible α-CA mutant strain showed increased intracellular gentamicin uptake in comparison to an isogenic strain encoding full-length, wild-type α-CA. We hypothesized that increased gentamicin uptake could be due to increased proton motive force (PMF), increased membrane permeability, or both. We observed increased intracellular ATP production in the α-CA mutant strain, suggesting increased PMF-driven gentamicin uptake contributed to the strain's gentamicin susceptibility. We also analyzed the membrane permeability and fatty acid composition of isogenic wild-type and α-CA mutant strains and found that the mutant displayed a membrane composition that was consistent with increased membrane permeability. Finally, we observed that exposure to the FDA-approved α-CA inhibitor acetazolamide lowered the gentamicin MIC of eight genetically diverse E. faecalis strains with intact α-CA but did not change the MIC of the α-CA mutant strain. These results suggest that α-CA mutation or inhibition increases PMF and alters membrane permeability, leading to increased uptake of gentamicin into E. faecalis. This connection could be exploited clinically to provide new combination therapies for patients with enterococcal infections. IMPORTANCE Enterococcal infections can be difficult to treat, and new therapeutic approaches are needed. In studying an E. faecalis clinical strain from an infected patient, we found that the bacteria were rendered hypersusceptible to aminoglycoside antibiotics through a mutation that disrupted the α-CA. Our follow-on work suggested two different ways that α-CA disruption causes increased gentamicin accumulation in E. faecalis: increased proton motive force-powered uptake and increased membrane permeability. We also found that a mammalian CA inhibitor could sensitize a variety of E. faecalis strains to killing with gentamicin. Given that mammalian CA inhibitors are frequently used to treat conditions such as glaucoma, hypertension, and epilepsy, our findings suggest that these "off-the-shelf" inhibitors could also be useful partner antibiotics for the treatment of E. faecalis infections.

Enhanced Care Units: Guidance on development and implementation within Acute Medicine.

The Society for Acute Medicine (SAM) and Intensive Care Society (ICS) have produced joint guidance on the standards of care and infrastructure required to deliver enhanced care within Acute Medicine. The cohort of patients this relates to are in the most part already being looked after on the AMU, but co-location and providing enhanced monitoring and nursing input will ensure safe, high-quality care can be delivered to them. We strongly support the development of enhanced care units, whilst clearly acknowledging that they are not a replacement for critical care where that is indicated. Enhanced care and critical care complement each other and will help foster the close working between the two specialties that modern acute care requires. This guidance draws on expertise and existing relevant guidance from the two societies, alongside that from the Faculty of Intensive Care Medicine (FICM), British Thoracic Society (BTS), National Institute for Health and Care Excellence (NICE) and NHS England / Improvement (NHSE/I). We recognise this is an area with limited evidence and so will aim to review it regularly as the knowledge and experience in this area increases.

The use of subjective cognitive complaints for detecting mild cognitive impairment in older adults across cultural and linguistic groups: A comparison of the Cognitive Function Instrument to the Montreal Cognitive Assessment.

INTRODUCTION: This pilot study aims to explore the psychometric properties of the Cognitive Function Instrument (CFI) as a measure of subjective cognitive complaints (SCC) and its performance in distinguishing mild cognitive impairment (MCI) from normal control (NC) compared to an objective cognitive screen (Montreal Cognitive Assessment [MoCA]). METHODS: One hundred ninety-four community-dwelling non-demented older adults with racial/ethnic diversity were included. Unidimensionality and internal consistency of the CFI were examined using factor analysis, Cronbach's alpha, and McDonald's omega. Logistic regression models and receiver operating characteristic (ROC) analysis were used to examine the performance of CFI. RESULTS: The CFI demonstrated adequate internal consistency; however, the fit for a unidimensional model was suboptimal. The CFI distinguished MCI from NC alone or in combination with MoCA. ROC analysis showed comparable performance of the CFI and the MoCA. DISCUSSION: Our findings support the use of CFI as a brief and easy-to-use screen to detect MCI in culturally/linguistically diverse older adults. HIGHLIGHT: What is the key scientific question or problem of central interest of the paper? Subjective cognitive complaints (SCCs) are considered the earliest sign of dementia in older adults. However, it is unclear if SCC are equivalent in different cultures. The Cognitive Function Instrument (CFI) is a 14-item measure of SCC. This study provides pilot data suggesting that CFI is sensitive for detecting mild cognitive impairment in a cohort of older adults with racial/ethnic diversity. Comparing performance, CFI demonstrates comparable sensitivity to the Montreal Cognitive Assessment, an objective cognitive screening test. Overall, SCC may provide a non-invasive, easy-to-use method to flag possible cognitive impairment in both research and clinical settings.

County-Level Life Expectancy Change: A Novel Metric for Monitoring Public Health.

Life expectancy (LE) is a core measure of population health. Studies have confirmed the predictive importance of modifiable determinants on LE, but less is known about their association with LE change over time at the US county level. In addition, we explore the predictive association of LE change with COVID-19 mortality. We used a linear regression model to calculate county-level annual LE change from 2011 to 2016, and categorized LE change (≤-0.1 years change per year as decreasing, ≥0.1 years as increasing, otherwise no change). A multinomial regression model was used to determine the association between modifiable determinants of health indicators from the County Health Rankings and LE change. A Poisson regression model was used to evaluate the relationship between change in life expectancy and COVID-19 mortality through September 2021. Among 2943 counties, several modifiable determinants of health were significantly associated with odds of being in increasing LE or decreasing LE counties, including adult smoking, obesity, unemployment, and proportion of children in poverty. The presence of an increasing LE in 2011-2016, as compared to no change, was significantly associated with a 5% decrease in COVID-19 mortality between 2019 and 2021 (ß = 0.953, 95% CI: 0.943, 0.963). We demonstrated that change in LE at the county level is a useful metric for tracking public health progress, measuring the impact of public health initiatives, and gauging preparedness and vulnerability for future public health emergencies.

Smartphone ownership and usage in Chinese- and English-speaking older adults.

BACKGROUND: Data collection by smartphone is becoming more widespread in healthcare research. Previous studies reported racial/ethnical differences in the use of digital health technology. However, cross-language group comparison (Chinese- and English-speaking older adults) were not performed in these studies. This project will expand to smartphone technology use in diverse older populations with a focus on Chinese American older adults who are monolingual Chinese-speakers. METHOD: The Alzheimer's Disease Research Center (ADRC) at Icahn School of Medicine at Mount Sinai (ISMMS) evaluates diverse older populations using National Alzheimer's Coordinating Center's Uniform Data Set (NACC UDS). The UDS has different language versions, including English and Chinese. The evaluation includes a medical examination, cognitive assessments, and a research blood draw. Smartphone ownership and usage were captured using a local questionnaire developed by our ADRC. The questionnaire, available in English and Chinese, was administered by our ADRC coordinators during the COVID-19 pandemic. Multivariate analysis of variance (MANOVA) was used to examine differences in technology ownership and usages between the two language groups, while controlling for age, gender, education, and cognitive status (measured by Clinical Dementia Rating). RESULT: 33 Chinese- and 117 English-speaking older adults who received a diagnosis of normal cognition or mild cognitive impairment at consensus were included in the data analysis. Results reveal a high prevalence of smartphone ownership in our Chinese- (100%) and English-speaking older participants (86.3%). Participants in both language groups use mobile technology for a wide range of purposes, such as getting news and other information (Chinese=90.9%; English=87.2%), sending/receiving text (Chinese=97.0%; English=96.6%), watching videos/TV shows (Chinese=78.8%; English=69.2%), and taking classes (Chinese=57.5%; English=57.3%). However, Chinese-speaking older adults were less likely than English-speaking older adults to use mobile technology to post their own reviews or comments online (Chinese=9.1%; English=39.3%, p=0.001), download or purchase an app (Chinese=21.2%; English=70.9%, p<0.001), track health/ fitness via apps/website (Chinese=12.1%; English=47.9%, p<0.001) and manage/receive medical care (Chinese=15.2%; English=67.5%, p<0.001). CONCLUSION: Our findings highlight potential barriers to smartphone usage in Chinese American older adults with limited English proficiency. The results have implications for how smartphone technology can be used in clinical practice and aging research.

Associations of Plasma CD36 and Body Fat Distribution.

CONTEXT: CD36 is a class B scavenger-receptor involved in the uptake of fatty acids in liver and adipose tissue. It is unknown whether plasma CD36 levels are related to liver fat content or adipose tissue in the general population. METHODS: We measured plasma CD36 from 575 participants of the community-based PopGen cohort who underwent MRI to quantify visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver signal intensity (LSI), a proxy for liver fat content. Nonalcoholic fatty liver disease (NAFLD) was defined as LSI ≥3.0 in the absence of high alcohol intake. The relations between plasma CD36 and body mass index (BMI), VAT, SAT, LSI, and NAFLD were evaluated via multivariable-adjusted linear and logistic regression analysis. RESULTS: Plasma CD36 concentrations were correlated with BMI (r = 0.11; P = 0.01), SAT (r = 0.16; P < 0.001), and VAT (r = 0.15, P < 0.001) but not with LSI (P = 0.44). In multivariable-adjusted regression models, mean BMI values rose across CD36 quartiles [quartile 1 (Q1), 27.8 kg/m2; Q4, 28.9 kg/m2; P-trend = 0.013). Similarly, VAT (Q1, 4.13 dm3; Q4, 4.71 dm3; P-trend < 0.001), and SAT (Q1, 7.61 dm3; Q4, 8.74 dm3; P-trend < 0.001) rose across CD36 quartiles. Plasma CD36 concentrations were unrelated to LSI (P-trend = 0.36) and NAFLD (P-trend = 0.64). Participants with NAFLD and elevated alanine aminotransferase (ALT), a marker for liver damage, had higher CD36 compared with participants with NAFLD and normal ALT. CONCLUSIONS: Higher plasma concentrations of CD36 were associated with greater general and abdominal adiposity but not with liver fat content or NAFLD in this community-based sample. However, plasma CD36 may reflect more severe liver damage in NAFLD.

Copanlisib: An Intravenous Phosphatidylinositol 3-Kinase (PI3K) Inhibitor for the Treatment of Relapsed Follicular Lymphoma.

Objective: To review the mechanism of action, clinical efficacy, safety, dosage, administration, and role of copanlisib in the treatment of relapsed follicular lymphoma (FL). Data Sources: Sources of information were identified through searches of PubMed (August 2014 to January 2019) using the key terms copanlisib, Aliqopa, PI3K inhibitor, and BAY 80-6946. Unpublished abstract information was obtained from the American Society of Clinical Oncology. Study Selection and Data Extraction: Review articles and studies in the English language evaluating the pharmacology, efficacy, and safety of copanlisib were included. Data Synthesis: Copanlisib is the first intravenous phosphatidylinositol 3-kinase (PI3K) inhibitor approved for the treatment of relapsed FL in patients who have received at least 2 prior systemic therapies. The safety and efficacy of copanlisib has been studied in the multicenter, single-arm, phase II CHRONOS-1 study. The results reported for FL patients were an objective response rate of 59%, a complete response of 14%, median duration of response of 22.6 months, and median progression-free survival of 11.2 months. The most common adverse events reported were hyperglycemia and hypertension, which were infusion related and transient. Relevance to Patient Care and Clinical Practice: Copanlisib is unique in that it is a pan-class I PI3K inhibitor with preferential inhibitory activity against the PI3K-α and PI3K-δ isoforms. It has a more favorable safety profile than the other agents in its class with no late-onset toxicities. Conclusions: Copanlisib provides an alternative option for patients with relapsed FL. It is safe and effective and has an acceptable toxicity profile.

DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial.

BACKGROUND: We have developed a Trivalent DNA vaccine for influenza consisting of three plasmids expressing haemagglutinin from different seasonal influenza virus strains delivered using PMED (particle mediated epidermal delivery). We set out to determine whether this vaccine (with and without a molecular adjuvant DNA Encoded Immunostimulator-Labile Toxin (DEI-LT)) could protect subjects from a controlled influenza virus challenge. METHODS: Healthy adult subjects were screened for susceptibility to infection with influenza A/H3 Panama/2007/99 then vaccinated with 4microg Trivalent influenza DNA vaccine, 2microg Trivalent influenza DNA vaccine plus DEI-LT or placebo. Safety and serological responses to vaccination were assessed and on Day 56 subjects were challenged with A/H3 Panama/2007/99 virus. RESULTS: Vaccination with 4microg Trivalent or 2microg Trivalent/DEI-LT was well tolerated and induced antibody responses to two of the three influenza virus vaccine strains. Post challenge, subjects in the 4microg Trivalent group (N=27) showed reductions in disease symptoms and viral shedding compared to placebo (N=27), with an overall vaccine efficacy of 41% (95% confidence interval (CI)=?1.5, 67.7) for 'Any illness with or without fever' and 53% for 'Upper respiratory tract infection' (95% CI=8.0, 77.7). CONCLUSION: It was concluded that PMED vaccination with 4microg Trivalent influenza DNA vaccine was safe and elicited immunological responses that protected human subjects from influenza; this is the first report of protection of human subjects from disease by DNA vaccination.

Obstacles to bottom-up implementation of marine ecosystem management.

Ecosystem management (EM) offers a means to address multiple threats to marine resources. Despite recognition of the importance of stakeholder involvement, most efforts to implement EM in marine systems are the product of top-down regulatory control. We describe a rare, stakeholder-driven attempt to implement EM from the bottom up in San Juan County, Washington (U.S.A.). A citizens advisory group led a 2-year, highly participatory effort to develop an ecosystem-based management plan, guided by a preexisting conservation-planning framework. A key innovation was to incorporate social dimensions by designating both sociocultural and biodiversity targets in the planning process. Multiple obstacles hindered implementation of EM in this setting. Despite using a surrogate scheme, the information-related transaction costs of planning were substantial: information deficits prevented assessment of some biodiversity targets and insufficient resources combined with information deficits prevented scientific assessment of the sociocultural targets. Substantial uncertainty, practical constraints to stakeholder involvement, and the existence of multiple, potentially conflicting, objectives increased negotiation-related costs. Although information deficits and uncertainty, coupled with underinvestment in the transaction costs of planning, could reduce the long-term effectiveness of the plan itself, the social capital and momentum developed through the planning process could yield unforeseeable future gains in protection of marine resources. The obstacles we identified here will require early and sustained attention in efforts to implement ecosystem management in other grassroots settings.