Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of ...immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.
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•Chemical proteomics identifies cysteine reactivity changes in activated T cells•Chemical proteomics maps ligandable cysteines in diverse immune-relevant proteins•Cysteine-directed electrophilic compounds suppress T cells by distinct mechanisms•Electrophile-cysteine interactions promote the degradation of immune proteins
Integrated chemical proteomics and phenotypic screening furnishes a global portrait of cysteine reactivity and ligandability in primary human T cells and enables the discovery of electrophilic small molecules that suppress T cell activation and promote the degradation of immunomodulatory proteins.
IMPORTANCE: Socioeconomic differences in life expectancy, health, and disability have been found in European countries as well as in the US. Identifying the extent and pattern of health disparities, ...both within and across the US and England, may be important for informing public health and public policy aimed at reducing these disparities. OBJECTIVE: To compare the health of US adults aged 55 to 64 years with the health of their peers in England across the high and low ranges of income in each country. DESIGN, SETTING, AND PARTICIPANTS: Using data from the Health and Retirement Study (HRS) and the English Longitudinal Study of Ageing (ELSA) for 2008-2016, a pooled cross-sectional analysis of comparably measured health outcomes, with adjustment for demographic characteristics and socioeconomic status, was conducted. The analysis sample included community-dwelling adults aged 55 to 64 years from the HRS and ELSA, resulting in 46 887 person-years of observations. Data analysis was conducted from September 17, 2019, to May 12, 2020. EXPOSURES: Residence in the US or England and yearly income. MAIN OUTCOMES AND MEASURES: Sixteen health outcomes were compared, including 5 self-assessed outcomes, 3 directly measured outcomes, and 8 self-reported physician-diagnosed health conditions. RESULTS: This cross-sectional study included 12 879 individuals and 31 928 person-years from HRS (mean SD age, 59.2 2.8 years; 51.9% women) and 5693 individuals and 14 959 person-years from ELSA (mean SD age, 59.3 2.9 years; 51.0% women). After adjusting for individual-level demographic characteristics and socioeconomic status, a substantial health gap between lower-income and higher-income adults was found in both countries, but the health gap between the bottom 20% and the top 20% of the income distribution was significantly greater in the US than England on 13 of 16 measures. The adjusted US-England difference in the prevalence gap between the bottom 20% and the top 20% ranged from 3.6 percentage points (95% CI, 2.0-5.2 percentage points) in stroke to 9.7 percentage points (95% CI, 5.4-13.9 percentage points) for functional limitation. Among individuals in the lowest income group in each country, those in the US group vs the England group had significantly worse outcomes on many health measures (10 of 16 outcomes in the bottom income decile); the significant differences in adjusted prevalence of health problems in the US vs England for the bottom income decile ranged from 7.6% (95% CI, 6.0%-9.3%) vs 3.8% (95% CI, 2.6%-4.9%) for stroke to 75.7% (95% CI, 72.7%-78.8%) vs 59.5% (95% CI, 56.3%-62.7%) for functional limitation. Among individuals in the highest income group, those in the US group vs England group had worse outcomes on fewer health measures (4 of 16 outcomes in the top income decile); the significant differences in adjusted prevalence of health problems in the US vs England for the top income decile ranged from 36.9% (95% CI, 33.4%-40.4%) vs 30.0% (95% CI, 27.2%-32.7%) for hypertension to 35.4% (95% CI, 32.0%-38.7%) vs 22.5% (95% CI, 19.9%-25.1%) for arthritis. CONCLUSIONS AND RELEVANCE: For most health outcomes examined in this cross-sectional study, the health gap between adults with low vs high income appeared to be larger in the US than in England, and the health disadvantages in the US compared with England are apparently more pronounced among individuals with low income. Public policy and public health interventions aimed at improving the health of adults with lower income should be a priority in the US.
Loneliness is a growing public health concern worldwide. We characterized the association between cumulative loneliness and subsequent all-cause mortality, using data from 9,032 participants aged 50+ ...in the population-based US Health and Retirement Study (HRS) from 1996 to 2019. Loneliness status (yes; no) was measured biennially from 1996 to 2004, and we categorized the experience of cumulative loneliness over the 8-y period as never, one time point, two time points, and ≥three time points. A multivariable-adjusted age-stratified Cox proportional hazards regression model was fitted to examine the association between cumulative loneliness from 1996 to 2004 and all-cause mortality from 2004 to 2019. Excess deaths due to each category of cumulative loneliness were calculated. Compared to those who never reported loneliness from 1996 to 2004, participants experiencing loneliness at one time point, two time points, and ≥three time points respectively had 1.05 (95% CI: 0.96 to 1.15), 1.06 (95% CI: 0.95 to 1.19), and 1.16 (95% CI: 1.02 to 1.33) times higher hazards of mortality from 2004 to 2019 (
trend = 0.01). These results correspond to 106 (95% CI: 68 to 144), 202 (95% CI: 146 to 259), and 288 (95% CI: 233 to 343) excess deaths per 10,000 person-years, for those experiencing loneliness at each of one, two, or ≥three time points from 1996 to 2004. Cumulative loneliness in mid-to-later life may thus be a mortality risk factor with a notable impact on excess mortality. Loneliness may be an important target for interventions to improve life expectancy in the United States.
Abstract
Background
Clinical frailty among older adults admitted to intensive care has been proposed as an important determinant of patient outcomes. Among this group of patients, an acute episode of ...delirium is also common, but its relationship to frailty and increased risk of mortality has not been extensively explored. Therefore, the aim of this study was to explore the relationship between clinical frailty, delirium and hospital mortality of older adults admitted to intensive care.
Methods
This study is part of a Delirium in Intensive Care (Deli) Study. During the initial 6-month baseline period, clinical frailty status on admission to intensive care, among adults aged 50 years or more; acute episodes of delirium; and the outcomes of intensive care and hospital stay were explored.
Results
During the 6-month baseline period, 997 patients, aged 50 years or more, were included in this study. The average age was 71 years (IQR, 63–79); 55% were male (
n
= 537). Among these patients, 39.2% (95% CI 36.1–42.3%,
n
= 396) had a Clinical Frailty Score (CFS) of 5 or more, and 13.0% (
n
= 127) had at least one acute episode of delirium. Frail patients were at greater risk of an episode of delirium (17% versus 10%, adjusted rate ratio (
adj
RR) = 1.71, 95% confidence interval (CI) 1.20–2.43,
p
= 0.003), had a longer hospital stay (2.6 days, 95% CI 1–7 days,
p
= 0.009) and had a higher risk of hospital mortality (19% versus 7%,
adj
RR = 2.54, 95% CI 1.72–3.75,
p
< 0.001), when compared to non-frail patients. Patients who were frail and experienced an acute episode of delirium in the intensive care had a 35% rate of hospital mortality versus 10% among non-frail patients who also experienced delirium in the ICU.
Conclusion
Frailty and delirium significantly increase the risk of hospital mortality. Therefore, it is important to identify patients who are frail and institute measures to reduce the risk of adverse events in the ICU such as delirium and, importantly, to discuss these issues in an open and empathetic way with the patient and their families.
Socioeconomic differences in life expectancy, health, and disability have been found in European countries as well as in the US. Identifying the extent and pattern of health disparities, both within ...and across the US and England, may be important for informing public health and public policy aimed at reducing these disparities.
To compare the health of US adults aged 55 to 64 years with the health of their peers in England across the high and low ranges of income in each country.
Using data from the Health and Retirement Study (HRS) and the English Longitudinal Study of Ageing (ELSA) for 2008-2016, a pooled cross-sectional analysis of comparably measured health outcomes, with adjustment for demographic characteristics and socioeconomic status, was conducted. The analysis sample included community-dwelling adults aged 55 to 64 years from the HRS and ELSA, resulting in 46 887 person-years of observations. Data analysis was conducted from September 17, 2019, to May 12, 2020.
Residence in the US or England and yearly income.
Sixteen health outcomes were compared, including 5 self-assessed outcomes, 3 directly measured outcomes, and 8 self-reported physician-diagnosed health conditions.
This cross-sectional study included 12 879 individuals and 31 928 person-years from HRS (mean SD age, 59.2 2.8 years; 51.9% women) and 5693 individuals and 14 959 person-years from ELSA (mean SD age, 59.3 2.9 years; 51.0% women). After adjusting for individual-level demographic characteristics and socioeconomic status, a substantial health gap between lower-income and higher-income adults was found in both countries, but the health gap between the bottom 20% and the top 20% of the income distribution was significantly greater in the US than England on 13 of 16 measures. The adjusted US-England difference in the prevalence gap between the bottom 20% and the top 20% ranged from 3.6 percentage points (95% CI, 2.0-5.2 percentage points) in stroke to 9.7 percentage points (95% CI, 5.4-13.9 percentage points) for functional limitation. Among individuals in the lowest income group in each country, those in the US group vs the England group had significantly worse outcomes on many health measures (10 of 16 outcomes in the bottom income decile); the significant differences in adjusted prevalence of health problems in the US vs England for the bottom income decile ranged from 7.6% (95% CI, 6.0%-9.3%) vs 3.8% (95% CI, 2.6%-4.9%) for stroke to 75.7% (95% CI, 72.7%-78.8%) vs 59.5% (95% CI, 56.3%-62.7%) for functional limitation. Among individuals in the highest income group, those in the US group vs England group had worse outcomes on fewer health measures (4 of 16 outcomes in the top income decile); the significant differences in adjusted prevalence of health problems in the US vs England for the top income decile ranged from 36.9% (95% CI, 33.4%-40.4%) vs 30.0% (95% CI, 27.2%-32.7%) for hypertension to 35.4% (95% CI, 32.0%-38.7%) vs 22.5% (95% CI, 19.9%-25.1%) for arthritis.
For most health outcomes examined in this cross-sectional study, the health gap between adults with low vs high income appeared to be larger in the US than in England, and the health disadvantages in the US compared with England are apparently more pronounced among individuals with low income. Public policy and public health interventions aimed at improving the health of adults with lower income should be a priority in the US.
IMPORTANCE: Estimating the effects of dementia on care use and financial outcomes is timely, as the population with dementia will more than double in the next few decades. OBJECTIVE: To determine the ...incremental changes associated with dementia in regard to older adults’ care use and assess financial consequences for individuals, families, and society. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included propensity score matching on national, longitudinal data using extensive baseline variables of sociodemographic characteristics, economic status, family availability, health conditions, disability status, and outpatient care use among 2 groups of US adults aged 55 years or older who did not have dementia. In total, 2387 adults experienced the onset of dementia during the 2-year follow-up (dementia group) and 2387 adults did not (control group). Participants were followed up for 8 years from the baseline. Data were analyzed from February 2021 to August 2023. EXPOSURE: Dementia determined based on Langa-Weir classification. MAIN OUTCOMES AND MEASURES: Outcomes of care use included monthly care hours from family and unpaid helpers, in-home medical services, hospital stay, and nursing facility stay. Financial outcomes included out-of-pocket medical costs, wealth, and the status of having Medicaid. RESULTS: Among the full sample, the mean (SD) age was 75.4 10.4 years, and 59.7% of participants were female. Care use was similar at baseline between the matched groups but was substantially greater for the dementia group vs control group in subsequent years, especially during the 2-year follow-up: 45 vs 13 monthly care hours from family and unpaid helpers, 548 of 2370 participants (23.1%) vs 342 of 2383 (14.4%) using in-home medical care, 1104 of 2369 (46.6%) vs 821 of 2377 (34.5%) with hospital stay, and 489 of 2375 (20.6%) vs 104 of 2384 (4.4%) using a nursing facility. The increase in use of a nursing facility was especially high if baseline family care availability was low. Over the 8-year follow-up in the dementia group, the 2-year out-of-pocket medical costs increased from $4005 to $10 006, median wealth was reduced from $79 339 to $30 490, and those enrolling in Medicaid increased from 379 of 2358 participants (16.1%) to 201 of 676 participants (29.7%). No statistically significant changes in financial outcomes were found in the control group. CONCLUSION AND RELEVANCE: This cohort study demonstrated that the incremental changes associated with dementia in regard to older adults’ long-term care and financial burden are substantial. Family care availability should be accounted for in a comprehensive assessment of predicting the effects of dementia.
Despite the important role that family members can play in dementia care, little is known about the association between the availability of family members and the type of care, informal (unpaid) or ...formal (paid), that is actually delivered to older adults with dementia in the US. Using data about older adults with dementia from the Health and Retirement Study, we found significantly lower spousal availability but greater adult child availability among women versus men, non-Hispanic Blacks versus non-Hispanic Whites, and people with lower versus higher socioeconomic status. Adults with dementia and disability who have greater family availability were significantly more likely to receive informal care and less likely to use formal care. In particular, the predicted probability of a community-dwelling adult moving to a nursing home during the subsequent two years was substantially lower for those who had a co-resident adult child (11 percent) compared with those who did not have a co-resident adult child but had at least one adult child living close (20 percent) and with those who have all children living far (23 percent). Health care policies on dementia should consider potential family availability in predicting the type of care that people with dementia will use and the potential disparities in consequences for them and their families.
Abstract
Objectives
Disability in the United States has not improved in recent decades. Comparing temporal trends in disability prevalence across different income groups, both within and between the ...United States and England, would inform public policy aimed at reducing disparities in disability.
Methods
Using the Health and Retirement Study and the English Longitudinal Study of Ageing, we estimated annual percent change from 2002 to 2016 in disability among community-dwelling adults (197,021 person-years of observations). Disability was defined based on self-report of limitations with 5 instrumental activities of daily living and 6 activities of daily living. We examined the trends by age and income quintile and adjusted for individual-level sociodemographic status and survey design.
Results
The adjusted annual percent change (AAPC) in disability prevalence declined significantly in both countries for ages 75 and older during 2002–2016. For ages 55–64 and 65–74, disability prevalence was unchanged in the United States but declined in England. Both countries experienced a widening gap in disability between low- and high-income adults among the younger age groups. For example, for those ages 55–64 in each country, there was no significant improvement in disability for the low-income group but a significant improvement for the high-income group (AAPC = −3.60; 95% confidence interval CI; −6.57, −0.63 for the United States; AAPC = −6.06; 95% CI −8.77, −3.35 for England).
Discussion
Improvements in disability were more widespread in England than in the United States between 2002 and 2016. In both countries, the disparity in disability between low- and high-income adults widened for middle-aged adults. Policies targeted at preventing disability among low-income adults should be a priority in both countries.
OBJECTIVE:Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of ...cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes.
METHODS:High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Wardʼs clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model.
RESULTS:There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal–dominant atrophy subtype (n = 52, ∼34.2%), (2) parietal-dominant subtype (n = 28, ∼18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features.
CONCLUSIONS:This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features.
The purpose of this study was to investigate if multi-domain cognitive training, especially robot-assisted training, alters cortical thickness in the brains of elderly participants. A controlled ...trial was conducted with 85 volunteers without cognitive impairment who were 60 years old or older. Participants were first randomized into two groups. One group consisted of 48 participants who would receive cognitive training and 37 who would not receive training. The cognitive training group was randomly divided into two groups, 24 who received traditional cognitive training and 24 who received robot-assisted cognitive training. The training for both groups consisted of daily 90-min-session, five days a week for a total of 12 weeks. The primary outcome was the changes in cortical thickness. When compared to the control group, both groups who underwent cognitive training demonstrated attenuation of age related cortical thinning in the frontotemporal association cortices. When the robot and the traditional interventions were directly compared, the robot group showed less cortical thinning in the anterior cingulate cortices. Our results suggest that cognitive training can mitigate age-associated structural brain changes in the elderly.
ClnicalTrials.gov NCT01596205.
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