Systolic Blood Pressure and Survival to Very Old Age: Results From the Women's Health Initiative.

BACKGROUND: The relationship between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine which SBP levels in women ≥65 years of age with or without blood pressure medication were associated with the highest probability of surviving to 90 years of age. METHODS: The study population consisted of 16 570 participants enrolled in the Women's Health Initiative who were eligible to survive to 90 years of age by February 28, 2020, without a history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993 through 1998) and then annually through 2005. The outcome was defined as survival to 90 years of age with follow-up. Absolute probabilities of surviving to 90 years of age were estimated for all combinations of SBP and age using generalized additive logistic regression modeling. The SBP that maximized survival was estimated for each age, and a 95% CI was generated. RESULTS: During a median follow-up of 19.8 years, 9723 of 16 570 women (59%) survived to 90 years of age. Women with an SBP between 110 and 130 mm Hg at attained ages of 65, 70, 75, and 80 years had a 38% (95% CI, 34%-48%), 54% (52%-56%), 66% (64%-67%), or 75% (73%-78%) absolute probability to survive to 90 years of age, respectively. The probability of surviving to 90 years of age was lower for greater SBP levels. Women at the attained age of 80 years with 0%, 20%, 40%, 60%, 80%, or 100% time in therapeutic range (defined as an SBP between 110 and 130 mm Hg) had a 66% (64%-69%), 68% (67%-70%), 71% (69%-72%), 73% (71%-74%), 75% (72%-77%), or 77% (74%-79%) absolute survival probability to 90 years of age. CONCLUSIONS: For women >65 years of age with low cardiovascular disease and other chronic disease risk, an SBP level <130 mm Hg was found to be associated with longevity. These findings reinforce current guidelines targeting an SBP target <130 mm Hg in older women.

Forecasting daily total pollen concentrations on a global scale.

BACKGROUND: There is evidence that global anthropogenic climate change may be impacting floral phenology and the temporal and spatial characteristics of aero-allergenic pollen. Given the extent of current and future climate uncertainty, there is a need to strengthen predictive pollen forecasts. METHODS: The study aims to use CatBoost (CB) and deep learning (DL) models for predicting the daily total pollen concentration up to 14 days in advance for 23 cities, covering all five continents. The model includes the projected environmental parameters, recent concentrations (1, 2 and 4 weeks), and the past environmental explanatory variables, and their future values. RESULTS: The best pollen forecasts include Mexico City (R2(DL_7) ≈ .7), and Santiago (R2(DL_7) ≈ .8) for the 7th forecast day, respectively; while the weakest pollen forecasts are made for Brisbane (R2(DL_7) ≈ .4) and Seoul (R2(DL_7) ≈ .1) for the 7th forecast day. The global order of the five most important environmental variables in determining the daily total pollen concentrations is, in decreasing order: the past daily total pollen concentration, future 2 m temperature, past 2 m temperature, past soil temperature in 28-100 cm depth, and past soil temperature in 0-7 cm depth. City-related clusters of the most similar distribution of feature importance values of the environmental variables only slightly change on consecutive forecast days for Caxias do Sul, Cape Town, Brisbane, and Mexico City, while they often change for Sydney, Santiago, and Busan. CONCLUSIONS: This new knowledge of the ecological relationships of the most remarkable variables importance for pollen forecast models according to clusters, cities and forecast days is important for developing and improving the accuracy of airborne pollen forecasts.

The association of painful and non-painful morbidities with frailty: a cross sectional analysis of a cohort of community dwelling older people in England.

INTRODUCTION: The association between chronic pain and frailty might indicate that pain is an independent driver of frailty but might alternatively be explained by inclusion within frailty identification tools of morbidities that commonly lead to chronic pain. This research examines the extent to which the association of pain with frailty might be attributed to morbidities. METHODS: A cross-sectional analysis of older people in a UK cohort with or at risk of musculoskeletal problems or frailty (Investigating Musculoskeletal Health and Wellbeing study), used multivariable logistic regression and Z-tests to assess the degrees of associations of pain (McGill Pain Rating Index), and painful and non-painful morbidity counts with frailty (modified FRAIL questionnaire). RESULTS: Data were from 2,185 participants, 56% female, median age 73 (range 60 to 96) years. 430 (20%) participants were classified as frail. In a fully adjusted standardised model, pain (aOR 2.07 (95%CI 1.83 to 2.33) and 'any' morbidity aOR (1.74 (95%CI 1.54 to 1.97) were both significantly associated with frailty. When morbidity was subclassified as painful or non-painful, painful (aOR 1.48 (95%CI 1.30 to 1.68) and non-painful (aOR1.39 (95%CI 1.24 to 1.56)) morbidities each were associated with frailty, as also was pain (aOR 2.07 (95%CI 1.83 to 2.34, p < 0.001). CONCLUSIONS: Pain is associated with frailty, over and above any effect of painful and non-painful morbidities. This forms the justification for future research which focuses on pain management in the identification, prevention, and treatment of frailty.

Higher airborne pollen concentrations correlated with increased SARS-CoV-2 infection rates, as evidenced from 31 countries across the globe.

Pollen exposure weakens the immunity against certain seasonal respiratory viruses by diminishing the antiviral interferon response. Here we investigate whether the same applies to the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is sensitive to antiviral interferons, if infection waves coincide with high airborne pollen concentrations. Our original hypothesis was that more airborne pollen would lead to increases in infection rates. To examine this, we performed a cross-sectional and longitudinal data analysis on SARS-CoV-2 infection, airborne pollen, and meteorological factors. Our dataset is the most comprehensive, largest possible worldwide from 130 stations, across 31 countries and five continents. To explicitly investigate the effects of social contact, we additionally considered population density of each study area, as well as lockdown effects, in all possible combinations: without any lockdown, with mixed lockdown-no lockdown regime, and under complete lockdown. We found that airborne pollen, sometimes in synergy with humidity and temperature, explained, on average, 44% of the infection rate variability. Infection rates increased after higher pollen concentrations most frequently during the four previous days. Without lockdown, an increase of pollen abundance by 100 pollen/m3 resulted in a 4% average increase of infection rates. Lockdown halved infection rates under similar pollen concentrations. As there can be no preventive measures against airborne pollen exposure, we suggest wide dissemination of pollen-virus coexposure dire effect information to encourage high-risk individuals to wear particle filter masks during high springtime pollen concentrations.

Exploring the association between park size and crime.

This study explored the link between park size and crime risk in Alabama, analyzing 564 parks across 73 cities with populations over 10,000. Park dimensions were measured using Google Earth Pro, and crime data, covering violent and property crimes, were sourced from Applied Geographic Solutions. Additional data on population density, mental health prevalence, social vulnerability, and alcohol expenditure (indicative of affluence) were obtained from the U.S. Census Bureau, CDC, and ESRI. A multiple regression analysis revealed a significant negative association between park size and crime risk, meaning that larger park sizes tended to have lower crime rates. Key covariates-mental health, social vulnerability, and alcohol spending- were also significantly related to crime rates. Our findings have policy implications for local governments and community organizations seeking to reduce crime rates.

Acute downregulation of emerin alters actomyosin cytoskeleton connectivity and function.

Fetal lung fibroblasts contribute dynamic infrastructure for the developing lung. These cells undergo dynamic mechanical transitions, including cyclic stretch and spreading, which are integral to lung growth in utero. We investigated the role of the nuclear envelope protein emerin in cellular responses to these dynamic mechanical transitions. In contrast to control cells, which briskly realigned their nuclei, actin cytoskeleton, and extracellular matrices in response to cyclic stretch, fibroblasts that were acutely downregulated for emerin showed incomplete reorientation of both nuclei and actin cytoskeleton. Emerin-downregulated fibroblasts were also aberrantly circular in contrast to the spindle-shaped controls and exhibited an altered pattern of filamentous actin organization that was disconnected from the nucleus. Emerin knockdown was also associated with reduced myosin light chain phosphorylation during cell spreading. Interestingly, emerin-downregulated fibroblasts also demonstrated reduced fibronectin fibrillogenesis and production. These findings indicate that nuclear-cytoskeletal coupling serves a role in the dynamic regulation of cytoskeletal structure and function and may also impact the transmission of traction force to the extracellular matrix microenvironment.

Immune response to ART initiation in advanced HIV infection.

OBJECTIVES: Our objective was to compare the immunological responses to commonly used antiretroviral therapy (ART) regimens among people with advanced HIV in the USA and to assess virological outcomes and regimen persistence. METHODS: This study included ART-naïve adults with advanced HIV infection (CD4 cell count <200 cells/µL) initiating ART with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), boosted darunavir (bDRV), dolutegravir (DTG), or elvitegravir (EVG/c)-containing regimens between 1 January 2018 and 31 December 2020 in the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. Cox proportional hazards models and linear mixed models with random intercept were fit with inverse probability of treatment weighting. RESULTS: Overall, 1349 people with advanced HIV (816 B/F/TAF, 253 DTG, 146 EVG/c, 134 bDRV) were followed for a median of 22 months. Compared with B/F/TAF, a lower likelihood of achieving a CD4 cell count ≥200 cells/µL was observed with bDRV (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.60-0.96), DTG (HR 0.82; 95% CI 0.69-0.98), and EVG/c (HR 0.73; 95% CI 0.57-0.93). All groups had a similar pattern of CD4:CD8 ratio changes: a rapid increase in the first 6 months (ranging from +0.15 to +0.16 units), followed by a slower increase thereafter. Only 40 individuals (4%) achieved CD4:CD8 ratio normalization (≥1). B/F/TAF was associated with a faster time to virological suppression (viral load <200 copies/mL) and a slower time to discontinuation compared with other regimens. CONCLUSIONS: Among people with advanced HIV infection, B/F/TAF initiation was associated with faster CD4 cell count recovery and favourable virological outcomes compared with bDRV-, DTG-, and EVG/c-based regimens, although no difference was observed in CD4:CD8 ratio changes over time across regimens.

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.

BACKGROUND: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored. METHODS AND RESULTS: We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic. CONCLUSION: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

Improving Timeliness of Antibiotic Administration Using a Provider and Pharmacist Facing Sepsis Early Warning System in the Emergency Department Setting: A Randomized Controlled Quality Improvement Initiative.

OBJECTIVES: Results of pre-post intervention studies of sepsis early warning systems have been mixed, and randomized clinical trials showing efficacy in the emergency department setting are lacking. Additionally, early warning systems can be resource-intensive and may cause unintended consequences such as antibiotic or IV fluid overuse. We assessed the impact of a pharmacist and provider facing sepsis early warning systems on timeliness of antibiotic administration and sepsis-related clinical outcomes in our setting. DESIGN: A randomized, controlled quality improvement initiative. SETTING: The main emergency department of an academic, safety-net healthcare system from August to December 2019. PATIENTS: Adults presenting to the emergency department. INTERVENTION: Patients were randomized to standard sepsis care or standard care augmented by the display of a sepsis early warning system-triggered flag in the electronic health record combined with electronic health record-based emergency department pharmacist notification. MEASUREMENTS AND MAIN RESULTS: The primary process measure was time to antibiotic administration from arrival. A total of 598 patients were included in the study over a 5-month period (285 in the intervention group and 313 in the standard care group). Time to antibiotic administration from emergency department arrival was shorter in the augmented care group than that in the standard care group (median, 2.3 hr [interquartile range, 1.4-4.7 hr] vs 3.0 hr [interquartile range, 1.6-5.5 hr]; p = 0.039). The hierarchical composite clinical outcome measure of days alive and out of hospital at 28 days was greater in the augmented care group than that in the standard care group (median, 24.1 vs 22.5 d; p = 0.011). Rates of fluid resuscitation and antibiotic utilization did not differ. CONCLUSIONS: In this single-center randomized quality improvement initiative, the display of an electronic health record-based sepsis early warning system-triggered flag combined with electronic health record-based pharmacist notification was associated with shorter time to antibiotic administration without an increase in undesirable or potentially harmful clinical interventions.

Subjective cognitive decline and total energy intake: Talk too much?

The increasing longevity of the population has resulted in dementia becoming a leading cause of both death and disability. Dementia is not a single disease. Studies of rare Mendelian disorders have documented that Alzheimer's disease, the most common cause of dementia, is associated with a long incubation period from amyloid deposition to neurodegeneration to mild cognitive impairment and dementia. There are three broad hypotheses related to the causes of Alzheimer's dementia: (1) an aging process; (2) brain vascular disease; and (3) metabolic abnormalities associated with either increased production of amyloid-ß or decreased clearance from the brain. Therefore, research on the early stages of the dementia process are of high priority. This paper reports that higher energy intake in both the Nurses' Health Study and Health Professionals Follow-up Study is associated with very early symptoms that lead to mild cognitive impairment and dementia. The results are very interesting but hard to interpret because they also show that higher energy intake is not related to body mass index, a very unusual observation. A likely hypothesis is that there is an association between reporting of dietary intake and subjective symptoms, i.e. reporting bias, accounting for their results.

Inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2.

Cells express a family of three inositol hexakisphosphate kinases (IP6Ks). Although sharing the same enzymatic activity, individual IP6Ks mediate different cellular processes. Here we report that IP6K3 is enriched at the leading edge of migrating cells where it associates with dynein intermediate chain 2 (DIC2). Using immunofluorescence microscopy and total internal reflection fluorescence microscopy, we found that DIC2 and IP6K3 are recruited interdependently to the leading edge of migrating cells, where they function coordinately to enhance the turnover of focal adhesions. Deletion of IP6K3 causes defects in cell motility and neuronal dendritic growth, eventually leading to brain malformations. Our results reveal a mechanism whereby IP6K3 functions in coordination with DIC2 in a confined intracellular microenvironment to promote focal adhesion turnover.

Low untreated systolic blood pressure over 18 years is associated with survival free of dementia age 90.

INTRODUCTION: We hypothesized that lower untreated systolic blood pressure (SBP) would be associated with a lower risk of dementia and death up to age 95. METHODS: SBP measured between 2000 and 2006 was evaluated in relationship to dementia risk and brain biomarkers from 2009-2020 (n = 177) in the Gingko Evaluation of Memory Study (GEMS), mean age 95 in 2020. Participants had measurements of brain amyloid beta (Aß) and repeat clinical-cognitive evaluations every 6 months. RESULTS: By 2020, only 9 of 177 patients (5%) were alive and cognitively unimpaired (CU). Mean SBP from 2000 to 2006 was 120 mm Hg for nine alive/CU, 125 mm Hg for alive/mild cognitive impairment (MCI), and 130 mm Hg for alive/dementia (P = .03). The amount of Aß was directly related to SBP levels. In multivariate analysis, Aß+ in 2009 and thinner cortex were significant predictors of dementia. Excluding Aß, SBP became a significant predictor of dementia. DISCUSSION: Low SBP untreated by antihypertensive medications was associated with significant decreased risk of dementia and less Aß.

What are the factors associated with neighborhood park visits and health in Alabama? A cross-sectional study using a path model.

This study seeks to examine the effect of the characteristics of park users, park characteristics, and the neighborhood environment on park visits and the resultant perceived health status of residents living in Alabama, US. One hundred and eighty-nine participants, representing residents from 49 counties in Alabama, were recruited via a random-digit dial method to complete a telephone survey related to park visits. Data collection spanned 11 months. Results from the path analysis indicated a few significant direct effects: park location and body mass index (BMI) were the only two factors significantly associated with park visits, with race being marginally significant; and work status was significantly associated with perceived health. Our findings suggest park proximity, and high BMI are related to park visits and work status is related to perceived health among Alabamians. It is recommended that more neighborhood parks are needed for promoting Alabamians to visit them more frequently.

Randomized Trial Evaluation of the Benefits and Risks of Menopausal Hormone Therapy Among Women 50-59 Years of Age.

The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy postmenopausal women aged 50-79 years at 40 US clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens and 16,608 participants with a uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over a (median) 18-year follow-up period (1993-2016), risk for a global index (defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality) was reduced with conjugated equine estrogens with a hazard ratio of 0.82 (95% confidence interval: 0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture, and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (95% confidence interval: 0.95, 1.19) were nonsignificant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59 years of age, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

Estrogen, brain structure, and cognition in postmenopausal women.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-ß in cognitively unimpaired older adults.

INTRODUCTION: Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aß deposition in oldest-old cognitively unimpaired (CU) adults. METHODS: A large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aß deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aß status and hippocampal volume, were incorporated to assess conditional associations. RESULTS: At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aß burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aß deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions. DISCUSSION: In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aß deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aß pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.

Leaf characteristics of rice cultivars with a stronger yield response to projected increases in CO2 concentration.

Rising levels of atmospheric carbon dioxide (CO2 ) could, potentially, be exploited as a means to increase seed yield and maintain food security, especially for cereal grains. Although there have been multiple cultivar trials indicating that significant yield variation occurs, the basis for these differences has not been entirely elucidated. Here, we focus on two rice cultivars that differed in field trials to their yield sensitivity to elevated CO2 : Yangdao6hao (YD6), and Wuyunjing23 (W23) to assess whether observed yield differences (YD6 > W23) were associated with concurrent changes in leaf-level characteristics. At ambient levels of CO2 , leaf net photosynthesis (A) of YD6 was compatible with that of W23. However, at elevated CO2 , A was higher for YD6 relative to W23. The stability of leaf Rubisco content, biochemical characteristics (Vc,max, and Jmax ), nitrogen enzymatic activity, and chlorophyll concentration differed significantly, with greater values observed for YD6 relative to W23 at elevated CO2 . While such results are consistent with other studies, we also demonstrate that a higher ratio of carbon sinks (seed) to carbon sources (leaf), were linked to increases in cytokinins, and slower flag leaf senescence for the YD6 relative to the W23 cultivar at elevated CO2 . While additional data for a broader genetic selection are needed, the current study suggests a link between source/sink carbon assimilation, maintenance of photosynthetic biochemistry, and slower leaf senescence for rice cultivars that show a stronger yield response to projected CO2 levels. This information, in turn, may provide suitable metrics for future CO2 selection among rice cultivars.

Comparison of Chemical Structure and Cell Morphology Information for Multitask Bioactivity Predictions.

The understanding of the mechanism-of-action (MoA) of compounds and the prediction of potential drug targets play an important role in small-molecule drug discovery. The aim of this work was to compare chemical and cell morphology information for bioactivity prediction. The comparison was performed using bioactivity data from the ExCAPE database, image data (in the form of CellProfiler features) from the Cell Painting data set (the largest publicly available data set of cell images with ∼30,000 compound perturbations), and extended connectivity fingerprints (ECFPs) using the multitask Bayesian matrix factorization (BMF) approach Macau. We found that the BMF Macau and random forest (RF) performance were overall similar when ECFPs were used as compound descriptors. However, BMF Macau outperformed RF in 159 out of 224 targets (71%) when image data were used as compound information. Using BMF Macau, 100 (corresponding to about 45%) and 90 (about 40%) of the 224 targets were predicted with high predictive performance (AUC > 0.8) with ECFP data and image data as side information, respectively. There were targets better predicted by image data as side information, such as ß-catenin, and others better predicted by fingerprint-based side information, such as proteins belonging to the G-protein-Coupled Receptor 1 family, which could be rationalized from the underlying data distributions in each descriptor domain. In conclusion, both cell morphology changes and chemical structure information contain information about compound bioactivity, which is also partially complementary, and can hence contribute to in silico MoA analysis.

ENGAGE and EMERGE: Truth and consequences?

The potential benefit of the anti-amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the future of anti-amyloid drug therapies. The two trials of 18-month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high-dose EMERGE trial initially also showed no benefit but with longer follow-up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti-amyloid drugs is very substantial as well as the brain amyloid-AD-dementia hypothesis.

Ophthalmic conditions associated with dementia risk: The Cardiovascular Health Study.

INTRODUCTION: Ophthalmic conditions and dementia appear to overlap and may share common pathways, but research has not differentiated dementia subtypes. METHODS: Diagnoses of cataracts, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma were based on medical histories and International Classification of Diseases, Ninth Revision (ICD-9) codes for 3375 participants from the Cardiovascular Health Study. Dementia, including Alzheimer's disease (AD) and vascular dementia (VaD), was classified using standardized research criteria. RESULTS: Cataracts were associated with AD (hazard ratio [HR] = 1.34; 95% confidence interval [CI] = 1.01-1.80) and VaD/mixed dementia (HR = 1.41; 95% CI = 1.02-1.95). AMD was associated with AD only (HR = 1.87; 95% CI = 1.13-3.09), whereas DR was associated with VaD/mixed dementia only (HR = 2.63; 95% CI = 1.10-6.27). DISCUSSION: Differential associations between specific ophthalmic conditions and dementia subtypes may elucidate pathophysiologic pathways. Lack of association between glaucoma and dementia was most surprising from these analyses.