Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity.

The regenerative potential of neural stem cells (NSCs) declines during aging, leading to cognitive dysfunctions. This decline involves up-regulation of senescence-associated genes, but inactivation of such genes failed to reverse aging of hippocampal NSCs. Because many genes are up-regulated or down-regulated during aging, manipulation of single genes would be insufficient to reverse aging. Here we searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. We found that a combination of inducing the zinc finger transcription factor gene Plagl2 and inhibiting Dyrk1a, a gene associated with Down syndrome (a genetic disorder known to accelerate aging), rejuvenated aged hippocampal NSCs, which already lost proliferative and neurogenic potential. Such rejuvenated NSCs proliferated and produced new neurons continuously at the level observed in juvenile hippocampi, leading to improved cognition. Epigenome, transcriptome, and live-imaging analyses indicated that this gene combination induces up-regulation of embryo-associated genes and down-regulation of age-associated genes by changing their chromatin accessibility, thereby rejuvenating aged dormant NSCs to function like juvenile active NSCs. Thus, aging of NSCs can be reversed to induce functional neurogenesis continuously, offering a way to treat age-related neurological disorders.

Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma.

Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.

The Evolving Practice of Hospital at Home in the United States.

Hospital at Home (HaH) provides hospital-level services in the home to eligible patients who would otherwise require facility-based hospitalization. In the last two decades, studies have shown that HaH can improve patient outcomes and satisfaction and reduce hospital readmissions. Improved technology and greater experience with the model have led to expansion in the scope of patients served and services provided by the model, but dissemination in the United States has been hampered by lack of insurance coverage until recently. HaH is likely at the tipping point for wide adoption in the United States. To realize its full benefits, HaH will need to continue volume expansion to achieve culture change in clinical practice as facilitated by increased insurance coverage, technological advancements, and improved workforce expertise. It is also essential that HaH programs maintain high-quality acute hospital care, ensure that their benefits can be accessed by hard-to-reach rural populations, and continue to advance health equity.

Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors.

Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a+Eomes+ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a+Eomes+ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.

Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling.

Tyrosine kinase 2 (TYK2) is involved in type I interferon (IFN-I) signaling through IFN receptor 1 (IFNAR1). This signaling pathway is crucial in the early antiviral response and remains incompletely understood on B cells. Therefore, to understand the role of TYK2 in B cells, we studied these cells under homeostatic conditions and following in vitro activation using Tyk2-deficient (Tyk2-/-) mice. Splenic B cell subpopulations were altered in Tyk2-/- compared to wild type (WT) mice. Marginal zone (MZ) cells were decreased and aged B cells (ABC) were increased, whereas follicular (FO) cells remained unchanged. Likewise, there was an imbalance in transitional B cells in juvenile Tyk2-/- mice. RNA sequencing analysis of adult MZ and FO cells isolated from Tyk2-/- and WT mice in homeostasis revealed altered expression of IFN-I and Toll-like receptor 7 (TLR7) signaling pathway genes. Flow cytometry assays corroborated a lower expression of TLR7 in MZ B cells from Tyk2-/- mice. Splenic B cell cultures showed reduced proliferation and differentiation responses after activation with TLR7 ligands in Tyk2-/- compared to WT mice, with a similar response to lipopolysaccharide (LPS) or anti-CD40 + IL-4. IgM, IgG, IL-10 and IL-6 secretion was also decreased in Tyk2-/- B cell cultures. This reduced response of the TLR7 pathway in Tyk2-/- mice was partially restored by IFNα addition. In conclusion, there is a crosstalk between TYK2 and TLR7 mediated by an IFN-I feedback loop, which contributes to the establishment of MZ B cells and to B cell proliferation and differentiation.

Randomized Field Trial to Assess the Safety and Efficacy of Dihydroartemisinin-Piperaquine for Seasonal Malaria Chemoprevention in School-Aged Children in Bandiagara, Mali.

BACKGROUND: Owing to the increased cases of malaria in older children, the World Health Organization has recently recommended extending seasonal malaria chemoprevention (SMC) to children >5 years of age and using other effective drugs for malaria. In this study, we report the safety and efficacy of dihydroartemisinin-piperaquine (DHA-PQ) for SMC in school-aged children in Mali. METHOD: This randomized, controlled trial included 345 participants aged 6-15 years randomized to receive DHA-PQ, sulfadoxine-pyrimethamine plus amodiaquine (SP-AQ), or no chemoprevention (albendazole) at a 1:1:1 ratio. Four rounds of SMC were conducted from September to December 2021. The participants were assessed 7 days after each round for safety and efficacy of the interventions. RESULTS: Abdominal pain (11.8% vs 29.2%), headache (11.2% vs 19.2%), and vomiting (5.7% vs 15.2%) were frequently reported in the DHA-PQ and SP-AQ arms. On Day 120 of follow up, the incidence of clinical malaria was 0.01 episodes/person-month in the DHA-PQ and SP-AQ arms and 0.17 episodes/person-month in the control arm (P < .0001). Gametocytes were detected in 37 participants in all arms. CONCLUSIONS: Children in DHA-PQ arm reported less adverse events compared to the SP-AQ arm. Both drugs were effective against clinical malaria and infection.

Menopause Status and Within-Group Differences in Chronological Age Affect the Functional Neural Correlates of Spatial Context Memory in Middle-Aged Females.

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife-a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged premenopausal and postmenopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal females (age range, 39.55-53.30 years; mean age, 44.28 years; SD age, 3.12 years) and 41 postmenopausal females (age range, 46.70-65.14 years; mean age, 57.56 years; SD age, 3.93 years). We found that postmenopausal status, and advanced age within postmenopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal cortices during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife.SIGNIFICANCE STATEMENT This is the first fMRI study to examine how premenopause and postmenopause status affect the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age-related and performance-related correlations with brain activity in inferior parietal, parahippocampal, and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at premenopause compared with postmenopause.

Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life. METHODS: Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011-2013) and 7 (2018-2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition. RESULTS: Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1-7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%. CONCLUSIONS: Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.

Supervised Exercise Training for Chronic Heart Failure With Preserved Ejection Fraction: A Scientific Statement From the American Heart Association and American College of Cardiology.

Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life. This success may be attributed, at least in part, to the pleiotropic effects of exercise, which may favorably affect the full range of abnormalities-peripheral vascular, skeletal muscle, and cardiovascular-that contribute to exercise intolerance in HFpEF. Accordingly, this scientific statement critically examines the currently available literature on the effects of exercise-based therapies for chronic stable HFpEF, potential mechanisms for improvement of exercise capacity and symptoms, and how these data compare with exercise therapy for other cardiovascular conditions. Specifically, data reviewed herein demonstrate a comparable or larger magnitude of improvement in exercise capacity from supervised exercise training in patients with chronic HFpEF compared with those with heart failure with reduced ejection fraction, although Medicare reimbursement is available only for the latter group. Finally, critical gaps in implementation of exercise-based therapies for patients with HFpEF, including exercise setting, training modalities, combinations with other strategies such as diet and medications, long-term adherence, incorporation of innovative and more accessible delivery methods, and management of recently hospitalized patients are highlighted to provide guidance for future research.

Serogroup B Invasive Meningococcal Disease in Older Adults Identified by Genomic Surveillance, England, 2022-2023.

We report a cluster of serogroup B invasive meningococcal disease identified via genomic surveillance in older adults in England and describe the public health responses. Genomic surveillance is critical for supporting public health investigations and detecting the growing threat of serogroup B Neisseria meningitidis infections in older adults.

A Segmented Regression Analysis of Household Income and Recurrent Falls Among Adults in a National Cohort Study.

Falls can have life-altering consequences for older adults, including extended recovery periods and compromised independence. Higher household income may mitigate the risk of falls by providing financial resources for mobility tools, remediation of environmental hazards, and needed supports, or it may buffer the impact of an initial fall on subsequent risk through improved assistance and care. Household income has not had a consistently observed association with falls in older adults; however, a segmented association may exist such that associations are attenuated above a certain income threshold. In this study, we utilized segmented negative binomial regression analysis to examine the association between household income and recurrent falls among 2,302 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study recruited between 2003 and 2007. Income-fall association segments separated by changes in slope were considered. Model results indicated a 2-segment association between household income and recurrent falls in the past year. In the range below the breakpoint, household income was negatively associated with the rate of recurrent falls across all age groups examined; in a higher income range (from $20,000-$49,999 to ≥$150,000), the association was attenuated (weaker negative trend) or reversed (positive trend). These findings point to potential benefits of ensuring that incomes for lower-income adults exceed the threshold needed to confer a reduced risk of recurrent falls.

Exercise to socialize? Bidirectional relationships between physical activity and loneliness in middle-aged and older American adults.

Physical inactivity and loneliness are both associated with health risks and can affect each other through various social and behavioral mechanisms. However, current evidence on this relationship is equivocal and mostly based on cross-sectional data. This longitudinal study aimed to determine whether current levels of physical activity (moderate and vigorous intensity) and loneliness are associated with future respective states of themselves and each other. We used data from waves 6-14 (2002-2018) of the Health and Retirement Study (n = 20 134) in a mixed-effects and random-intercept cross-lagged panel model. Analysis showed that current loneliness and physical activity were associated with each future respective state. Additionally, weekly participation in moderate-intensity, but not vigorous-intensity, physical activity was associated with a lower likelihood of becoming lonely in the future (relative risk [RR] = 0.94; 95% CI, 0.90-0.99). However, changes in physical activity were not associated with deviation from a person's typical level of loneliness (for vigorous intensity, mean deviation [MD] = 0.00; 95% CI: -0.04 to 0.03; for moderate-intensity, MD = 0.01; 95% CI: -0.03 to 0.04). Loneliness was not associated with moderate- or vigorous-intensity physical activity in subsequent waves. This suggests that while lower physical activity levels can be associated with future loneliness, changing levels of physical activity has little impact on loneliness at the individual level.

Involvement of Fgf2-mediated tau protein phosphorylation in cognitive deficits induced by sevoflurane in aged rats.

OBJECTIVE: Anesthetics have been linked to cognitive alterations, particularly in the elderly. The current research delineates how Fibroblast Growth Factor 2 (Fgf2) modulates tau protein phosphorylation, contributing to cognitive impairments in aged rats upon sevoflurane administration. METHODS: Rats aged 3, 12, and 18 months were subjected to a 2.5% sevoflurane exposure to form a neurotoxicity model. Cognitive performance was gauged, and the GEO database was employed to identify differentially expressed genes (DEGs) in the 18-month-old cohort post sevoflurane exposure. Bioinformatics tools, inclusive of STRING and GeneCards, facilitated detailed analysis. Experimental validations, both in vivo and in vitro, examined Fgf2's effect on tau phosphorylation. RESULTS: Sevoflurane notably altered cognitive behavior in older rats. Out of 128 DEGs discerned, Fgf2 stood out as instrumental in regulating tau protein phosphorylation. Sevoflurane exposure spiked Fgf2 expression in cortical neurons, intensifying tau phosphorylation via the PI3K/AKT/Gsk3b trajectory. Diminishing Fgf2 expression correspondingly curtailed tau phosphorylation, neurofibrillary tangles, and enhanced cognitive capacities in aged rats. CONCLUSION: Sevoflurane elicits a surge in Fgf2 expression in aging rats, directing tau protein phosphorylation through the PI3K/AKT/Gsk3b route, instigating cognitive aberrations.

Chronotype and metabolic syndrome in midlife: findings from the Northern Finland Birth Cohort 1966.

Evening chronotype is known to be associated with various chronic diseases and cardiovascular risk factors. Metabolic syndrome is a group of conditions that together raise the risk of coronary heart disease, diabetes, stroke, and other serious health problems. Only a few studies have been published on the association between chronotype and metabolic syndrome in unselected population data, with conflicting results. The aim of this study was to evaluate the association between chronotype and metabolic syndrome at population level by using unselected Northern Finland Birth cohort 1966 (NFBC1966) database. The study population consists of participants with NFBC66 (n = 5,113, 57% female) at the age of 46 yr old. Chronotype was determined with shortened Morningness-Eveningness Questionnaires and expressed as morning (44%), intermediate (44%), and evening types (12%). Metabolic syndrome was determined according to the definition of International Diabetes Federation. One-way ANOVA, Kruskal-Walli's test, and χ2 tests were used to compare the chronotype groups, followed by logistic regression analysis (adjusted with alcohol consumption, smoking, marital status, level of education, and leisure-time physical activity). In women, the prevalence of metabolic syndrome was statistically significantly higher in the evening type group: 23, 24, and 34% for morning, intermediate, and evening groups, respectively (P < 0.001). In logistic regression analysis, evening chronotype was associated with higher risk of having metabolic syndrome (OR 1.5; CI 95% 1.2 to 2.0). In this population-based birth cohort study, the evening chronotype was independently associated with higher prevalence of metabolic syndrome in women.NEW & NOTEWORTHY Only a few studies have been conducted on the association between chronotype and metabolic syndrome in unselected population data, with conflicting results. In this population-based cohort study of 5,113 participants, the evening chronotype associated with metabolic syndrome in women when there was no such association in men. The result supports a previous South Korean population study of 1,620 participants, in which the association was also found in women, but not in men.

Information technology-supported integrated health service for older adults in long-term care settings.

BACKGROUND: To examine the effectiveness and safety of a data sharing and comprehensive management platform for institutionalized older patients. METHODS: We applied information technology-supported integrated health service platform to patients who live at long-term care hospitals (LTCHs) and nursing homes (NHs) with cluster randomized controlled study. We enrolled 555 patients aged 65 or older (461 from 7 LTCHs, 94 from 5 NHs). For the intervention group, a tablet-based platform comprising comprehensive geriatric assessment, disease management, potentially inappropriate medication (PIM) management, rehabilitation program, and screening for adverse events and warning alarms were provided for physicians or nurses. The control group was managed with usual care. Co-primary outcomes were (1) control rate of hypertension and diabetes, (2) medication adjustment (PIM prescription rate, proportion of polypharmacy), and (3) combination of potential quality-of-care problems (composite quality indicator) from the interRAI assessment system which assessed after 3-month of intervention. RESULTS: We screened 1119 patients and included 555 patients (control; 289, intervention; 266) for analysis. Patients allocated to the intervention group had better cognitive function and took less medications and PIMs at baseline. The diabetes control rate (OR = 2.61, 95% CI 1.37-4.99, p = 0.0035), discontinuation of PIM (OR = 4.65, 95% CI 2.41-8.97, p < 0.0001), reduction of medication in patients with polypharmacy (OR = 1.98, 95% CI 1.24-3.16, p = 0.0042), and number of PIMs use (ꞵ = - 0.27, p < 0.0001) improved significantly in the intervention group. There was no significant difference in hypertension control rate (OR = 0.54, 95% CI 0.20-1.43, p = 0.2129), proportion of polypharmacy (OR = 1.40, 95% CI 0.75-2.60, p = 0.2863), and improvement of composite quality indicators (ꞵ = 0.03, p = 0.2094). For secondary outcomes, cognitive and motor function, quality of life, and unplanned hospitalization were not different significantly between groups. CONCLUSIONS: The information technology-supported integrated health service effectively reduced PIM use and controlled diabetes among older patients in LTCH or NH without functional decline or increase of healthcare utilization. TRIAL REGISTRATION: Clinical Research Information Service, KCT0004360. Registered on 21 October 2019.

The quality of care delivered to residents in long-term care in Australia: an indicator-based review of resident records (CareTrack Aged study).

BACKGROUND: This study estimated the prevalence of evidence-based care received by a population-based sample of Australian residents in long-term care (LTC) aged ≥ 65 years in 2021, measured by adherence to clinical practice guideline (CPG) recommendations. METHODS: Sixteen conditions/processes of care amendable to estimating evidence-based care at a population level were identified from prevalence data and CPGs. Candidate recommendations (n = 5609) were extracted from 139 CPGs which were converted to indicators. National experts in each condition rated the indicators via the RAND-UCLA Delphi process. For the 16 conditions, 236 evidence-based care indicators were ratified. A multi-stage sampling of LTC facilities and residents was undertaken. Trained aged-care nurses then undertook manual structured record reviews of care delivered between 1 March and 31 May 2021 (our record review period) to assess adherence with the indicators. RESULTS: Care received by 294 residents with 27,585 care encounters in 25 LTC facilities was evaluated. Residents received care for one to thirteen separate clinical conditions/processes of care (median = 10, mean = 9.7). Adherence to evidence-based care indicators was estimated at 53.2% (95% CI: 48.6, 57.7) ranging from a high of 81.3% (95% CI: 75.6, 86.3) for Bladder and Bowel to a low of 12.2% (95% CI: 1.6, 36.8) for Depression. Six conditions (skin integrity, end-of-life care, infection, sleep, medication, and depression) had less than 50% adherence with indicators. CONCLUSIONS: This is the first study of adherence to evidence-based care for people in LTC using multiple conditions and a standardised method. Vulnerable older people are not receiving evidence-based care for many physical problems, nor care to support their mental health nor for end-of-life care. The six conditions in which adherence with indicators was less than 50% could be the focus of improvement efforts.

Adherence to guideline-recommended care of late-onset hypertension in females versus males: A population-based cohort study.

BACKGROUND: Sex-based disparities in cardiovascular outcomes may be improved with appropriate hypertension management. OBJECTIVE: To compare the evidence-based evaluation and management of females with late-onset hypertension compared to males in the contemporary era. METHODS: Design: Retrospective population-based cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Residents aged ≥66 years with newly diagnosed hypertension between January 1, 2010, and December 31, 2017. EXPOSURE: Sex (female vs. male). OUTCOMES AND MEASURES: We used Poisson and logistic regression to estimate adjusted sex-attributable differences in the performance of guideline-recommended lab investigations. We estimated adjusted differences in time to the prescription of, and type of, first antihypertensive medication prescribed between females and males, using Cox regression. RESULTS: Among 111,410 adults (mean age 73 years, 53% female, median follow-up 6.8 years), females underwent a similar number of guideline-recommended investigations (adjusted incidence rate ratio, 0.997 [95% confidence interval [CI] 0.99-1.002]) compared to males. Females were also as likely to complete all investigations (0.70% females, 0.77% males; adjusted odds ratio, 0.96 [95% CI 0.83-1.11]). Females were slightly less likely to be prescribed medication (adjusted hazard ratio [aHR] 0.98 [95% CI 0.96-0.99]) or, among those prescribed, less likely to be prescribed first-line medication (aHR, 0.995 [95% CI 0.994-0.997]). CONCLUSIONS: Compared to males, females with late-onset hypertension were equally likely to complete initial investigations with comparable prescription rates. These findings suggest that there may be no clinically meaningful sex-based differences in the initial management of late-onset hypertension to explain sex-based disparities in cardiovascular outcomes.

Trend in prevalence, associated risk factors, and longitudinal outcomes of sarcopenia in China: A national cohort study.

AIMS: To estimate the contemporary trend in the prevalence of sarcopenia and evaluate its risk factors and the longitudinal associations with multiple chronic conditions and mortality among Chinese middle-aged and older adults. METHODS: This was a nationwide, prospective cohort study using data from the China Health and Retirement Longitudinal Study. The definition of sarcopenia was based on the Asian Working Group for Sarcopenia 2019 algorithm. In the cross-sectional analysis, we estimated the trend in the weighted prevalence of sarcopenia from 2011 to 2015 and examined the associated risk factors for sarcopenia severity in 2011. In the longitudinal analysis, we assessed the longitudinal associations between sarcopenia and 14 chronic conditions and mortality during a 9-year follow-up. RESULTS: The weighted prevalence of sarcopenia remained consistently high in the overall population from 2011 (15.9%, 95% confidence intervals [CI]: 15.1, 16.6) to 2015 (15.0%, 95% CI: 14.3, 15.6; p for trend = 0.075). A range of risk factors were independently associated with the severity of sarcopenia, including older age, female sex, lower socioeconomic status, smoking status, malnutrition, and several chronic conditions. Possible sarcopenic and sarcopenic individuals had higher odds of several chronic conditions (i.e., heart disease, chronic lung disease, and memory-related disease) and increased risks of mortality (possible sarcopenia: odds ratios (OR): 1.66, 95% CI: 1.37, 2.00; sarcopenia: OR: 1.69, 95% CI: 1.36, 2.11) in 9 years of follow-up. CONCLUSIONS: The prevalence of sarcopenia remained consistently high in the investigated population. Various risk factors were significantly associated with a higher prevalence of sarcopenia. Sarcopenic individuals had higher odds of several chronic conditions and increased risks of mortality, highlighting that the urgent need for dedicated efforts to improve the management of sarcopenic patients.

Senescence-Targeted and NAD+-Dependent SIRT1-Activated Nanoplatform to Counteract Stem Cell Senescence for Promoting Aged Bone Regeneration.

Age-related bone defects are a leading cause of disability and mortality in elderly individuals, and targeted therapy to delay the senescence of bone marrow-derived mesenchymal stem cells (MSCs) has emerged as a promising strategy to rejuvenate bone regeneration in aged scenarios. More specifically, activating the nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) pathway is demonstrated to effectively counteract MSC senescence and thus promote osteogenesis. Herein, based on an inventively identified senescent MSC-specific surface marker Kremen1, a senescence-targeted and NAD+ dependent SIRT1 activated nanoplatform is fabricated with a dual delivery of resveratrol (RSV) (SIRT1 promoter) and nicotinamide riboside (NR, NAD+ precursor). This targeting nanoplatform exhibits a strong affinity for senescent MSCs through conjugation with anti-Kremen1 antibodies and enables specifically responsive release of NR and RSV in lysosomes via senescence-associated ß-galactosidase-stimulated enzymatic hydrolysis of the hydrophilic chain. Furthermore, this nanoplatform performs well in promoting aged bone formation both in vitro and in vivo by boosting NAD+, activating SIRT1, and delaying MSC senescence. For the first time, a novel senescent MSC-specific surface marker is identified and aged bone repair is rejuvenated by delaying senescence of MSCs using an active targeting platform. This discovery opens up new insights for nanotherapeutics aimed at age-related diseases.

The effect of mailed outreach on FIT completion among patients aged 45-50 in a safety net healthcare system.

PURPOSE: Colorectal cancer screening is recommended starting at age 45, but there has been little research on strategies to promote screening in patients younger than 50. METHODS: An outreach program quasi-randomly assigned patients aged 45-50 without recent fecal immunochemical test (FIT), colonoscopy or contraindications to screening to two intervention arms: electronic outreach with email and text (electronic outreach only) versus electronic outreach plus mailed outreach with FIT, an instructional letter and a prepaid return envelope (mailed + electronic outreach). In response to known disparities in screening uptake, all Black patients were assigned to receive mailed + electronic outreach. RESULTS: Among patients quasi-randomly assigned to an intervention (non-Black patients), the 180-day FIT completion rate was 18.8% in the electronic outreach only group (n = 1,318) and 25.0% in the mailed + electronic outreach group (n = 1,364) (difference 6.2% [95% CI 3.0, 9.4]). FIT completion was 16.6% among Black patients (n = 469), 8.4% (95% CI 4.1, 12.6) lower than among non-Black patients also assigned to mailed + electronic outreach. CONCLUSION: Among patients aged 45-50, mailed + electronic outreach had a greater effect on FIT completion than electronic outreach alone. Crossover between intervention groups likely lead to an underestimation of the effect of mailed outreach.