Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology.

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer's mouse model with late plaque development. In 18-month-old APPNL-F/NL-F knockin mice, with and without the Alzheimer's disease risk mutation Trem2R47H/R47H, we report that expression of 38/55 PIGs have plaque-induced microglial upregulation, with a subset only upregulating in microglia directly contacting plaques. For seven PIGs, including Trem2, this upregulation is prevented in APPNL-F/NL-FTrem2R47H/R47H mice. These TREM2-dependent genes are all involved in phagocytic and degradative processes that we show correspond to a decrease in phagocytic markers and an increase in the density of small plaques in Trem2-mutated mice. Furthermore, despite the R47H mutation preventing increased Trem2 gene expression, TREM2 protein levels and microglial density are still marginally increased on plaques. Hence, both microglial contact with plaques and functioning TREM2 are necessary for microglia to respond appropriately to amyloid pathology.

Continuity of Care Among Postmenopausal Women With Cardiometabolic Diseases in the United States Early During the COVID-19 Pandemic: Findings From the Women's Health Initiative.

BACKGROUND: In response to the COVID-19 pandemic, public health measures, including stay-at-home orders, were widely instituted in the United States by March 2020. However, few studies have evaluated the impact of these measures on continuity of care among older adults living with chronic diseases. METHODS: Beginning in June 2020, participants of the national Women's Health Initiative (WHI) (N = 64 061) were surveyed on the impact of the pandemic on various aspects of their health and well-being since March 2020, including access to care appointments, medications, and caregivers. Responses received by November 2020 (response rate = 77.6%) were tabulated and stratified by prevalent chronic diseases, including hypertension, type 2 diabetes, and cardiovascular disease (CVD). RESULTS: Among 49 695 respondents (mean age = 83.6 years), 70.2% had a history of hypertension, 21.8% had diabetes, and 18.9% had CVD. Half of the respondents reported being very concerned about the pandemic, and 24.5% decided against seeking medical care to avoid COVID-19 exposure. A quarter reported difficulties with getting routine care, and 45.5% had in-person appointments converted to telemedicine formats; many reported canceled (27.8%) or rescheduled (37.7%) appointments. Among those taking prescribed medication (88.0%), 9.7% reported changing their method of obtaining medications. Those living with and without chronic diseases generally reported similar changes in care and medication access. CONCLUSIONS: Early in the pandemic, many older women avoided medical care or adapted to new ways of receiving care and medications. Therefore, optimizing alternative services, like telemedicine, should be prioritized to ensure that older women continue to receive quality care during public health emergencies.

Out-of-Hospital Cardiac Arrest Bystander Defibrillator Search Time and Experience With and Without Directional Assistance: A Randomized Simulation Trial in a Community Setting.

INTRODUCTION: Probability of survival after out-of-hospital cardiac arrest (OHCA) doubles when a bystander initiates cardiopulmonary resuscitation and uses an automated external defibrillator (AED) rapidly. National, state, and community efforts have increased placement of AEDs in public spaces; however, bystander AED use remains less than 2% in the United States. Little is known about the effect of giving bystanders directional assistance to the closest public access AED. METHODS: We conducted 35 OHCA simulations using a life-sized manikin with participants aged 18 through 65 years who searched for public access AEDs in 5 zones on a university campus. Zones varied by challenges to pedestrian AED acquisition and number of fixed AEDs. Participants completed 2 searches-first unassisted and then with verbal direction to the closest AED-and we compared AED delivery times. We conducted pretest and posttest surveys. RESULTS: In all 5 zones, the median time from simulated OHCA onset to AED delivery was lower when the bystander received directional assistance. Time savings (minutes:seconds) varied by zone, ranging from a median of 0:53 (P = 0.14) to 3:42 (P = 0.02). Only 3 participants immediately located the closest AED without directional assistance; more than half reported difficulty locating an AED. CONCLUSIONS: These findings may inform strategies to ensure that AEDs are consistently marked and placed in visible, accessible locations. Continued emphasis on developing strategies to improve lay bystanders' ability to locate and use AEDs may improve AED retrieval times and OHCA outcomes.

Hepatitis C infection and chronic kidney disease among Hispanics/Latinos.

ABSTRACT: Viral infections, including hepatitis C, can cause secondary glomerular nephropathies. Studies suggest that hepatitis C virus infection (HCV+) is a risk factor for chronic kidney disease (CKD) but evidence of this relationship is lacking among Hispanics/Latinos. We examined the association between HCV+ and incident CKD in a prospective cohort of Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos. HCV+ was defined by detectable HCV antibodies with additional confirmation through HCV RNA or recombinant immunoblot assay testing. Incident CKD was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or sex-specific threshold for albuminuria measured during follow-up. We used Poisson regression to estimate incidence rate ratios (IRR) of CKD and changes in eGFR- or albuminuria-based risk stages, separately. We used linear regression to estimate associations with continuous, annualized changes in eGFR and albuminuria.Over a follow-up period of 5.9 years, 712 incident CKD events occurred among 10,430 participants. After adjustment for demographic characteristics and comorbidities, HCV+ was not associated with incident CKD, defined by eGFR and albuminuria thresholds (IRR 1.29, 95% Confidence Interval 0.61, 2.73). HCV+ was significantly associated with higher eGFR risk stages (IRR 2.39, 95% CI 1.47, 3.61) with most participants transitioning from stage G1 to G2. HCV+ was associated with a continuous, annualized eGFR decline of -0.69 mL/min/m2/year (95% CI -1.23, -0.16). This large, cohort study did not find evidence of a strong association between HCV+ and new-onset CKD among Hispanics/Latinos. HCV infection may not be associated with risk of CKD among Hispanics/Latinos, although treatment with direct-acting antivirals is recommended for all HCV+ individuals, including those with established CKD or end-stage kidney disease.

Urinary organophosphate ester concentrations in relation to ultra-processed food consumption in the general US population.

BACKGROUND: Ultra-processed foods are highly processed foods which are manufactured with industrial substances to increase convenience and palatability. Some organophosphate esters (OPEs) are used as flame retardants and plasticizers and have been detected in food samples, particularly processed foods. However, little is known about dietary sources of OPEs or whether higher consumption of ultra-processed foods increases exposures. OBJECTIVES: We evaluated whether higher consumption of ultra-processed food is associated with urinary OPE metabolite concentrations in a nationally representative sample of US children and adults. METHODS: Among 2242 participants (≥6 years) in the National Health and Nutrition Examination Survey (NHANES) 2013-2014, we used the NOVA classification system to calculate percent of total energy from ultra-processed food using a 24 h dietary recall. Concentrations of 7 OPE metabolites, including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), bis(2-chloroethyl) phosphate (BCEP), dibutyl phosphate (DBUP), di-p-cresyl phosphate (DPCP), 2,3,4,5-tetrabromobenzoic acid (TBBA), and bis(1-chloro-2-propyl) phosphate (BCPP) were measured in urine. We used multivariable linear or logistic regressions to examine associations per 10% higher total energy from ultra-processed foods with percent changes or prevalence of detectable levels of creatinine-standardized OPEs. RESULTS: In a model adjusting for only urinary creatinine, each 10% higher total energy from ultra-processed food was associated with 3.5% (95% CI: 0.7%, 6.3%) higher DPHP and 8.2% (95% CI: 4.6, 11.9%) higher BDCPP concentrations. However, none of the OPE metabolites was associated with ultra-processed food consumption in models adjusted for sociodemographic characteristics, health behaviors, and BMI (all p-values >0.05). Ultra-processed breads and tortillas; sauces, dressing, and gravies; and milk-based drinks were associated with higher concentrations of BDCPP while frozen and shelf-stable plate meals were associated with lower concentrations. Reconstituted meat or fish products and ultra-processed milk-based desserts were associated with greater odds of detectable levels of BCPP. CONCLUSION: While some food groups were associated with urinary OPE metabolite concentrations, ultra-processed foods do not appear to be a major source of current OPE exposure in the US.

Genomic Epidemiology of Major Extraintestinal Pathogenic Escherichia coli Lineages Causing Urinary Tract Infections in Young Women Across Canada.

BACKGROUND: A few extraintestinal pathogenic Escherichia coli (ExPEC) multilocus sequence types (STs) cause the majority of community-acquired urinary tract infections (UTIs). We examine the genomic epidemiology of major ExPEC lineages, specifically factors associated with intestinal acquisition. METHODS: A total of 385 women with UTI caused by E. coli across Canada were asked about their diet, travel, and other exposures. Genome sequencing was used to determine both ST and genomic similarity. Logistic regression was used to identify factors associated with the acquisition of and infection with major ExPEC STs relative to minor ExPEC STs. RESULTS: ST131, ST69, ST73, ST127, and ST95 were responsible for 54% of all UTIs. Seven UTI clusters were identified, but genomes from the ST95, ST127, and ST420 clusters exhibited as few as 3 single nucleotide variations across the entire genome, suggesting recent acquisition. Furthermore, we identified a cluster of UTIs caused by 6 genetically-related ST1193 isolates carrying mutations in gyrA and parC. The acquisition of and infection with ST69, ST95, ST127, and ST131 were all associated with increased travel. The consumption of high-risk foods such as raw meat or vegetables, undercooked eggs, and seafood was associated with acquisition of and infection with ST69, ST127, and ST131, respectively. CONCLUSIONS: Reservoirs may aid in the dissemination of pandemic ExPEC lineages in the community. Identifying ExPEC reservoirs may help prevent future emergence and dissemination of high-risk lineages within the community setting.

Ultra-processed food consumption and exposure to phthalates and bisphenols in the US National Health and Nutrition Examination Survey, 2013-2014.

BACKGROUND: Ultra-processed food has low nutritional quality, is associated with development of chronic diseases, and may increase exposure to chemicals used in food packaging and production. OBJECTIVES: To assess associations of ultra-processed food consumption with exposure to phthalates and bisphenols, including newer replacements, in the general U.S. METHODS: Among 2212 National Health and Nutrition Examination Survey (NHANES) 2013-2014 participants (≥6 years), we classified items reported in a 24-h dietary recall according to the NOVA food processing classification system and calculated energy intake from ultra-processed food. Urinary concentrations of mono-benzyl (MBzP), mono-(3-carboxypropyl) (MCPP), mono-(carboxyisononyl) (MCNP), mono-(carboxyisoctyl) (MCOP), and four metabolites of di(2-ethylhexyl) (∑DEHP) phthalates and bisphenols A, F, and S were measured in spot urine samples. We estimated percent changes in natural log creatinine-standardized concentrations per 10% higher energy from ultra-processed food in covariate-adjusted multivariable linear regression models. We examined effect measure modification by age group, race/ethnicity, and poverty:income ratio and assessed associations with minimally processed food intake. RESULTS: In adjusted models, higher energy from ultra-processed food was associated with higher urinary concentrations of MCPP, MCNP, and MCOP but not MBzP, ∑DEHP, or bisphenols. Each 10% higher energy from ultra-processed food was associated with 8.0% (95% CI: 5.6%, 10.3%) higher urinary MCOP concentrations, with a stronger association among children than adolescents or adults. Ultra-processed sandwiches/hamburgers, French fries/other potato products, and ice cream/pops were associated with higher concentrations of multiple chemicals. Higher energy from minimally processed food was associated with lower concentrations of MCPP, MCNP, MCOP, and bisphenols A and F. DISCUSSION: Ultra-processed food consumption may increase exposure to currently used phthalates. Additional research is needed to determine whether minimally processed food diets or changes in food production practices can reduce phthalate and bisphenol exposures and related health effects, particularly among children who are more vulnerable to toxicants and tend to consume more ultra-processed food than adults.

Hospitalization Risk among Older Adults with Chronic Kidney Disease.

INTRODUCTION: Chronic kidney disease (CKD) risk staging is based on estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR). However, the relationship between all-cause hospitalization risk and the current CKD staging system has not been well studied among older adults, despite a high prevalence of CKD and a high risk of hospitalization in old age. METHODS: Among 4,766 participants of the Atherosclerosis Risk in Communities study, CKD was staged according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, using creatinine-based eGFR (eGFRcr) and ACR. Incidence rates of all-cause hospitalization associated with each CKD risk group were analyzed using negative binomial regression. Additionally, cause-specific hospitalization risks for cardiovascular, infectious, kidney, and other diseases were estimated. The impacts of using cystatin C-based eGFR (eGFRcys) to estimate the prevalence of CKD and risks of hospitalization were also quantified. RESULTS: Participants experienced 5,548 hospitalizations and 29% had CKD. Hospitalization rates per 1,000 person-years according to KDIGO risk categories were 208-223 ("low risk"), 288-376 ("moderately increased risk"), 363-548 ("high risk"), and 499-1083 ("very high risk"). The increased risk associated with low eGFR and high ACR persisted in adjusted analyses, examinations of cause-specific hospitalizations, and when CKD was staged by eGFRcys or eGFRcr-cys, a combined equation based on both creatinine and cystatin C. In comparison to eGFRcr, staging by eGFRcys increased the prevalence of CKD to 50%, but hospitalization risks remained similarly high. DISCUSSION/CONCLUSION: In older adults, decreased eGFR, increased ACR, and KDIGO risk stages based on a combination of these measures, were strong risk factors for hospitalization. These relationships were consistent, regardless of the marker used to estimate GFR, but the use of cystatin C resulted in a substantially higher prevalence of CKD than the use of creatinine. Older adults in the population with very high risk stages of CKD have hospitalization rates exceeding 500 per 1,000 person-years.

Association Between Hypertension and Kidney Function Decline: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: The relationship between hypertension, antihypertension medication use, and change in glomerular filtration rate (GFR) over time among individuals with preserved GFR requires investigation. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 14,854 participants from the Atherosclerosis Risk in Communities (ARIC) Study. PREDICTORS: Baseline hypertension status (1987-1989) was categorized according to the 2017 American College of Cardiology/American Heart Association Clinical Practice Guideline as normal blood pressure, elevated blood pressure, stage 1 hypertension, stage 2 hypertension without medication, or stage 2 hypertension with medication. OUTCOMES: Slope of estimated GFR (eGFR) at 5 study visits over 30 years. ANALYTICAL APPROACH: Mixed models with random intercepts and random slopes were fit to evaluate the association between baseline hypertension status and slope of eGFR. RESULTS: At baseline, 13.2%, 7.3%, and 19.4% of whites and 15.8%, 14.9%, and 39.9% of African Americans had stage 1 hypertension, stage 2 hypertension without medication, and stage 2 hypertension with medication. Compared with those with normal blood pressure, the annual eGFR decline was greater in people with higher blood pressure (whites: elevated blood pressure, -0.11mL/min/1.73m2; stage 1 hypertension, -0.15mL/min/1.73m2; stage 2 hypertension without medication, -0.36mL/min/1.73m2; stage 2 hypertension with medication, -0.17mL/min/1.73m2; African Americans: elevated blood pressure, -0.21mL/min/1.73m2; stage 1 hypertension, -0.16mL/min/1.73m2; stage 2 hypertension without medication, -0.50mL/min/1.73m2; stage 2 hypertension with medication, -0.16mL/min/1.73m2). The 30-year predicted probabilities of developing chronic kidney disease stage G3a+with normal blood pressure, elevated blood pressure, stage 1 hypertension, stage 2 hypertension without medication, or stage 2 hypertension with medication among whites were 54.4%, 61.6%, 64.7%, 78.1%, and 70.9%, respectively, and 55.4%, 62.8%, 60.9%, 76.1%, and 66.6% among African Americans. LIMITATIONS: Slope estimated using a maximum of 5 eGFR assessments; differential loss to follow-up. CONCLUSIONS: Compared to normotension, baseline hypertension status was associated with faster kidney function decline over 30-year follow-up in a general population cohort. This difference was attenuated among people using antihypertensive medications.