Cumulative Systolic Blood Pressure and Incident Stroke Type Variation by Race and Ethnicity.

Importance: Stroke risk varies by systolic blood pressure (SBP), race, and ethnicity. The association between cumulative mean SBP and incident stroke type is unclear, and whether this association differs by race and ethnicity remains unknown. Objective: To examine the association between cumulative mean SBP and first incident stroke among 3 major stroke types-ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH)-and explore how these associations vary by race and ethnicity. Design, Setting, and Participants: Individual participant data from 6 US longitudinal cohorts (January 1, 1971, to December 31, 2019) were pooled. The analysis was performed from January 1, 2022, to January 2, 2024. The median follow-up was 21.6 (IQR, 13.6-31.8) years. Exposure: Time-dependent cumulative mean SBP. Main Outcomes and Measures: The primary outcome was time from baseline visit to first incident stroke. Secondary outcomes consisted of time to first incident IS, ICH, and SAH. Results: Among 40 016 participants, 38 167 who were 18 years or older at baseline with no history of stroke and at least 1 SBP measurement before the first incident stroke were included in the analysis. Of these, 54.0% were women; 25.0% were Black, 8.9% were Hispanic of any race, and 66.2% were White. The mean (SD) age at baseline was 53.4 (17.0) years and the mean (SD) SBP at baseline was 136.9 (20.4) mm Hg. A 10-mm Hg higher cumulative mean SBP was associated with a higher risk of overall stroke (hazard ratio [HR], 1.20 [95% CI, 1.18-1.23]), IS (HR, 1.20 [95% CI, 1.17-1.22]), and ICH (HR, 1.31 [95% CI, 1.25-1.38]) but not SAH (HR, 1.13 [95% CI, 0.99-1.29]; P = .06). Compared with White participants, Black participants had a higher risk of IS (HR, 1.20 [95% CI, 1.09-1.33]) and ICH (HR, 1.67 [95% CI, 1.30-2.13]) and Hispanic participants of any race had a higher risk of SAH (HR, 3.81 [95% CI, 1.29-11.22]). There was no consistent evidence that race and ethnicity modified the association of cumulative mean SBP with first incident stroke and stroke type. Conclusions and Relevance: The findings of this cohort study suggest that cumulative mean SBP was associated with incident stroke type, but the associations did not differ by race and ethnicity. Culturally informed stroke prevention programs should address modifiable risk factors such as SBP along with social determinants of health and structural inequities in society.

Serious bacterial infection risk in recently immunized febrile infants in the emergency department.

STUDY OBJECTIVES: Fever following immunizations is a common presenting chiefcomplaint among infants. The 2021 American Academy of Pediatrics (AAP) febrile infant clinical practice guidelines exclude recently immunized (RI) infants. This is a challenge for clinicians in the management of the febrile RI young infant. The objective of this study was to assess the prevalence of SBI in RI febrile young infants between 6 and 12 weeks of age. METHODS: This was a retrospective chart review of infants 6-12 weeks who presented with a fever ≥38 °C to two U.S. military academic Emergency Departments over a four-year period. Infants were considered recently immunized (RI) if they had received immunizations in the preceding 72 h prior to evaluation and not recently immunized (NRI) if they had not received immunizations during this time period. The primary outcome was prevalence of serious bacterial infection (SBI) further delineated into invasive-bacterial infection (IBI) and non-invasive bacterial infection (non-IBI) based on culture and/or radiograph reports. RESULTS: Of the 508 febrile infants identified, 114 had received recent immunizations in the preceding 72 h. The overall prevalence of SBI was 11.4% (95% CI = 8.9-14.6) in our study population. The prevalence of SBI in NRI infants was 13.7% (95% CI = 10.6-17.6) compared to 3.5% (95% CI = 1.1-9.3) in RI infants. The relative risk of SBI in the setting of recent immunizations was 0.3 (95% CI = 0.1-0.7). There were no cases of invasive-bacterial infections (IBI) in the RI group with all but one of the SBI being urinary tract infections (UTI). The single non-UTI was a case of pneumonia in an infant who presented with respiratory symptoms within 24 h of immunizations. CONCLUSION: The risk of IBI (meningitis or bacteremia) in RI infants aged 6 to 12 weeks is low. Non-IBI within the first 24 h following immunization was significantly lower than in febrile NRI infants. UTIs remain a risk in the RI population and investigation with urinalysis and urine culture should be encouraged. Shared decision making with families guide a less invasive approach to the care of these children. Future research utilizing a large prospective multi-center data registry would aid in further defining the risk of both IBI and non-IBI among RI infants.

Emerging therapeutic approaches for peritoneal metastases from gastrointestinal cancers.

Peritoneal metastases from gastrointestinal malignancies present difficult management decisions, with options consisting primarily of systemic chemotherapy or major surgery with or without hyperthermic intraperitoneal chemotherapy. Current research is investigating expanding therapeutic modalities, and the aim of this review is to provide an overview of the existing and emerging therapies for the peritoneal metastases from gastrointestinal cancers, primarily through the recent literature (2015 and newer). These include the current data with systemic therapy and cytoreduction with hyperthermic intraperitoneal or pressurized intraperitoneal aerosol chemotherapy, as well as novel promising modalities under investigation, including dominating oncolytic viral therapy and adoptive cellular, biologic, and bacteria therapy, or nanotechnology. The novel diverse strategies, although preliminary and preclinical in murine models, individually and collectively contribute to the treatment of peritoneal metastases, offering hope for improved outcomes and quality of life. We foresee that these evolving treatment approaches will facilitate the transfer of knowledge and data among studies and advance discovery of new drugs and optimized treatments for patients with peritoneal metastases.

Tumor and Peritoneum-Associated Macrophage Gene Signature as a Novel Molecular Biomarker in Gastric Cancer.

A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2TS, MRC1; MS4A4A; CD36; CCL13; CCL18; CCL23; SLC38A6; FGL2; FN1; MAF) and M1 (M1TS, CCR7; IL2RA; CXCL11; CCL19; CXCL10; PLA1A; PTX3) macrophages, and cytolytic T-lymphocytes (CTLTS, GZMA; GZMB; GZMH; GZMM; PRF1). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2TS expression was associated with histological types and later stages. Low M2TS expression was associated with significantly better 5-year OS and DFI. We validated M2TS in prospectively collected peritoneal fluid of a GC patient cohort (n = 28). Single-cell RNA sequencing was used for signature expression in CD68+CD163+ cells and the log-rank test compared OS. GC patients with high M2TS in CD68+CD163+ cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2TS was significantly and independently associated with survival. As an independent predictor of poor survival, M2TS may be prognostic in primary tumors and peritoneal fluid of GC patients.

A single-institutional experience with 36 children less than 5 kilograms supported with the Berlin Heart: Comparison of congenital versus acquired heart disease.

OBJECTIVES: We reviewed outcomes in all 36 consecutive children <5 kg supported with the Berlin Heart pulsatile ventricular assist device at the University of Florida, comparing those with acquired heart disease (n = 8) to those with congenital heart disease (CHD) (n = 28). METHODS: The primary outcome was mortality. The Kaplan-Meier method and log-rank tests were used to assess group differences in long-term survival after ventricular assist device insertion. T-tests using estimated survival proportions were used to compare groups at specific time points. RESULTS: Of 82 patients supported with the Berlin Heart at our institution, 49 (49/82 = 59.76%) weighed <10 kg and 36 (36/82 = 43.90%) weighed <5 kg. Of 36 patients <5 kg, 26 (26/36 = 72.22%) were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 36 patients <5 kg was [days]: median = 109, range = 4-305.) Eight out of 36 patients <5 kg had acquired heart disease, and all eight [8/8 = 100%] were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 8 patients <5 kg with acquired heart disease was [days]: median = 50, range = 9-130.) Twenty-eight of 36 patients <5 kg had congenital heart disease. Eighteen of these 28 [64.3%] were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 28 patients <5 kg with congenital heart disease was [days]: median = 136, range = 4-305.) For all 36 patients who weighed <5 kg: 1-year survival estimate after ventricular assist device insertion = 62.7% (95% confidence interval = 48.5-81.2%) and 5-year survival estimate after ventricular assist device insertion = 58.5% (95% confidence interval = 43.8-78.3%). One-year survival after ventricular assist device insertion = 87.5% (95% confidence interval = 67.3-99.9%) in acquired heart disease and 55.6% (95% confidence interval = 39.5-78.2%) in CHD, P = 0.036. Five-year survival after ventricular assist device insertion = 87.5% (95% confidence interval = 67.3-99.9%) in acquired heart disease and 48.6% (95% confidence interval = 31.6-74.8%) in CHD, P = 0.014. CONCLUSION: Pulsatile ventricular assist device facilitates bridge to transplantation in neonates and infants weighing <5 kg; however, survival after ventricular assist device insertion in these small patients is less in those with CHD in comparison to those with acquired heart disease.

Epstein Barr virus-directed T-cell therapy for refractory EBV-PTLD in a toddler post Orthotopic heart transplantation.

Epstein-Barr Virus (EBV) is a ubiquitous herpes type virus that is associated with post-transplant lymphoproliferative disorder (PTLD). Usual management includes reduction or cessation of immunosuppression and in some cases chemotherapy including rituximab. However, limited therapies are available if PTLD is refractory to rituximab. Several clinical trials have investigated the use of EBV-directed T cells in rituximab-refractory patients; however, data regarding response is scarce and inconclusive. Herein, we describe a patient with EBV-PTLD refractory to rituximab after orthotopic heart transplantation (OHT) requiring EBV-directed T-cell therapy. This article aims to highlight the unique and aggressive clinical presentation and progression of PTLD with utilization of EBV-directed T-cell therapy for management and associated pitfalls.

Navigating the post-Dobbs landscape: ethical considerations from a perinatal perspective.

Restrictive abortion laws have impacts reaching far beyond the immediate sphere of reproductive health, with cascading effects on clinical and ethical aspects of neonatal care, as well as perinatal palliative care. These laws have the potential to alter how families and clinicians navigate prenatal and postnatal medical decisions after a complex fetal diagnosis is made. We present a hypothetical case to explore the nexus of abortion care and perinatal care of fetuses and infants with life-limiting conditions. We will highlight the potential impacts of limited abortion access on families anticipating the birth of these infants. We will also examine the legally and morally fraught gray zone of gestational viability where both abortion and resuscitation of live-born infants can potentially occur, per parental discretion. These scenarios are inexorably impacted by the rapidly changing legal landscape in the U.S., and highlight difficult ethical dilemmas which clinicians may increasingly need to navigate.

Catalytic carbon-carbon bond cleavage in lignin via manganese-zirconium-mediated autoxidation.

Efforts to produce aromatic monomers through catalytic lignin depolymerization have historically focused on aryl-ether bond cleavage. A large fraction of aromatic monomers in lignin, however, are linked by various carbon-carbon (C-C) bonds that are more challenging to cleave and limit the yields of aromatic monomers from lignin depolymerization. Here, we report a catalytic autoxidation method to cleave C-C bonds in lignin-derived dimers and oligomers from pine and poplar. The method uses manganese and zirconium salts as catalysts in acetic acid and produces aromatic carboxylic acids as primary products. The mixtures of the oxygenated monomers are efficiently converted to cis,cis-muconic acid in an engineered strain of Pseudomonas putida KT2440 that conducts aromatic O-demethylation reactions at the 4-position. This work demonstrates that autoxidation of lignin with Mn and Zr offers a catalytic strategy to increase the yield of valuable aromatic monomers from lignin.

Cholestasis is associated with a higher rate of complications in both medical and surgical necrotizing enterocolitis.

OBJECTIVE: To evaluate the relationship between cholestasis and outcomes in medical and surgical necrotizing enterocolitis (NEC). STUDY DESIGN: A retrospective analysis of prospectively collected data from 1472 infants with NEC [455 medical (mNEC) and 1017 surgical (sNEC)] from the Children's Hospital Neonatal Database. RESULTS: The prevalence of cholestasis was lower in mNEC versus sNEC (38.2% vs 70.1%, p < 0.001). In both groups, cholestasis was associated with lower birth gestational age [mNEC: OR 0.79 (95% CI 0.68-0.92); sNEC: OR 0.86 (95% CI 0.79-0.95)] and increased days of parenteral nutrition [mNEC: OR 1.08 (95% CI 1.04-1.13); sNEC: OR 1.01 (95% CI 1.01-1.02)]. For both groups, the highest direct bilirubin was associated with the composite outcome mortality or length of stay >75th percentile [mNEC: OR 1.21 (95% CI 1.06-1.38); sNEC: OR 1.06 (95% CI 1.03-1.09)]. CONCLUSION: Cholestasis with both medical NEC and surgical NEC is associated with adverse patient outcomes including increased mortality or extreme length of stay.

Mid-Life Vascular Risk and Rate of Physical Function Decline Among Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Physical function and its decline in older age may be connected to treatable vascular risk factors in mid-life. This study aimed to evaluate whether these factors affect the underlying rate of decline. METHODS: This prospective cohort included 5 481 older adults aged 67-91 in the Atherosclerosis Risk in Communities Study (mean [standard deviation {SD}] age = 75.8 [5.0], 58% women, 21% Black race) without a history of stroke. The main outcome was the rate of Short Physical Performance Battery (SPPB) decline over a median late-life follow-up of 4.8 years. Primary mid-life (aged 45-64) exposures were Visit 1 hypertension (>140/90 mm Hg or treatment), diabetes (>126 mg/dL or treatment), high cholesterol (>240 mg/dL or treatment), and smoking, and number of decades of vascular risk exposure across Visits 1-4. RESULTS: The average adjusted rate of SPPB decline (points per 5 years) for older adults was -0.79 (confidence interval [CI]: -0.87, 0.71) and was accelerated by mid-life hypertension (+57% decline vs normotension: additional decline of -0.47, 95% CI: -0.64, -0.30), diabetes (+73% decline vs no diabetes: additional decline of -0.67, 95% CI: -1.09, -0.24), elevated systolic blood pressure (+17% decline per SD: -0.16, 95% CI: -0.23, -0.10), and elevated fasting blood glucose (+16% decline per SD: -0.015, 95% CI: -0.24, -0.06). Each decade greater mid-life exposure to hypertension (+32% decline: -0.93, 95% CI: -1.25, -0.61) and diabetes (+35% decline: -1.03, 95% CI: -1.68, -0.38) was associated with faster SPPB decline. CONCLUSIONS: Mid-life control of blood pressure and diabetes may offset aging-related functional decline.

Orthostatic Blood Pressure Change, Dizziness, and Risk of Dementia in the ARIC Study.

BACKGROUND: Abnormal orthostatic blood pressure (BP) regulation may result in cerebral hypoperfusion and brain ischemia and contribute to dementia. It may also manifest as early symptoms of the neurodegenerative process associated with dementia. The relationship between the magnitude and timing of orthostatic BP responses and dementia risk is not fully understood. METHODS: We conducted a prospective cohort analysis of the associations of orthostatic BP changes and self-reported orthostatic dizziness with the risk of dementia in the Atherosclerosis Risk in Communities study (ARIC). We calculated changes in BP from the supine to the standing position at 5 measurements taken within 2 minutes after standing during the baseline visit (1987-1989). The primary outcome was adjudicated dementia ascertained through 2019. RESULTS: Among 11 644 participants (mean [SD] age, 54.5 [5.7] years; 54.1% women; 25.9% Black), 2303 dementia cases were identified during a median follow-up of 25.9 years. Large decreases in systolic BP from the supine to standing position measured at the first 2 measurements ≈30 and 50 seconds after standing, but not afterward, were associated with orthostatic dizziness and a higher risk of dementia. Comparing a decrease in systolic BP of ≤-20 or >-20 to -10 mm Hg to stable systolic BP (>-10 to 10 mm Hg) at the first measurement, the adjusted hazard ratios were 1.22 (95% CI, 1.01-1.47) and 1.10 (95% CI, 0.97-1.25), respectively. CONCLUSIONS: Abnormal orthostatic BP regulation, especially abrupt drops in BP within the first minute, might be early risk markers for the development of dementia. Transient early orthostatic hypotension warrants more attention in clinical settings.

Timing of Cognitive Test Score Decline Prior to Incident Dementia Diagnosis in Blacks and Whites: The Atherosclerosis Risk in Communities Neurocognitive Study.

INTRODUCTION: Commonly occurring dementias include those of Alzheimer's, vascular, and mixtures of these and other pathologies. They are believed to evolve over many years, but that time interval has been difficult to establish. Our objective was to determine how many years in advance of a dementia diagnosis cognitive scores begin to change. METHODS: 14,086 dementia-free ARIC participants underwent a cognitive exam at baseline visit 2 (1990-1992, mean age 57 ± 5.72), and 11,244 at visit 4 (1996-1998), 5,640 at visit 5 (2011-2013), and 3,574 at visit 6 (2016-2017) with surveillance for dementias of all-causes combined. Within 5-year intervals after each visit, we compared performance on the Delayed Word Recall Test (DWRT), the Digit Symbol Substitution Test (DSST), the Word Fluency Test (WFT), and the combined mean of three cognitive tests at baseline in participants who were diagnosed with dementia within each interval versus those who survived the interval without a dementia diagnosis. Z-scores were adjusted for demographics and education in separate regression models for each visit. We plotted adjusted z-score means by time interval following each visit. RESULTS: During follow-up 3,334, 2,821, 1,218, and 329 dementia cases were ascertained after visits 2, 4, 5, and 6, respectively. Adjusted DWRT z-scores were significantly lower 20-25 years before dementia than those who did not experience dementia within 25 years. DSST z-scores were significantly lower at 25-30 years and 3-test combination z-scores were significantly lower as early as 30-31 years before onset. The difference between dementia and non-dementia group in the visit 2 3-test combination z-score was -0.20 at 30-31 years prior to dementia diagnosis. As expected, differences between the dementia and non-dementia groups increased closer to the time of dementia occurrence, up to their widest point at 0-5 years prior to dementia diagnosis. The difference between dementia and non-dementia groups in the visit 2 3-test combination z-score at 0-5 years was -0.90. WFT z-score differences were smaller than for the DSST or DWRT and began later. Patterns were similar in Black and White participants. CONCLUSION: DWRT, DSST, and combined 3-test z-scores were significantly lower more than 20 years prior to diagnosis in the dementia group versus the non-dementia group. Findings contribute to our knowledge of the long prodromal period in Blacks and Whites.

Factors Associated with Poor Olfaction and Olfactory Decline in Older Adults in the ARIC Neurocognitive Study.

Olfactory function has significant implications for human health, but few risk factors for olfactory decline have been identified. We examined the factors associated with olfactory status and decline over five years in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. A 12-item odor identification test was used to assess olfaction in 6053 participants in 2011-2013 (ARIC visit 5, mean age: 75.6, 41% male, 23% Black race) and in 3235 participants in 2016-2017 (visit 6). We used Poisson regression models to examine cross-sectional associations of a range of potential factors with the total odor identification errors (mean errors: 2.8 ± 2.4) in visit 5 participants. We used mixed-effect Poisson regression to examine associations with olfactory decline between visits 5 and 6. We also examined associations with visit 5 anosmia prevalence (847 cases, 14%) and incident anosmia between the two visits (510 cases, 16%) using Poisson models. Older age, male sex, lower education, Black race, APOE ε4 alleles, and diabetes were associated with higher odor identification errors and higher anosmia prevalence, and greater physical activity and hypertension with better olfaction. Age, male sex, lower education, Black race, APOE ε4 allele, and vitamin B12 levels were associated with incident anosmia over 5 years. Older age was associated with faster olfactory decline. Future studies with longer follow-ups are warranted.

Outcomes of Children Supported With Pulsatile Paracorporeal Ventricular Assist Device: Congenital Versus Acquired Heart Disease.

BACKGROUND: We reviewed the outcomes of 82 consecutive pediatric patients (less than 18 years of age) supported with the Berlin Heart ventricular assist device (VAD), comparing those with congenital heart disease (CHD; n = 44) with those with acquired heart disease (AHD; n = 37). METHODS: The primary outcome was mortality after VAD insertion. Kaplan-Meier methods and log-rank tests were used to assess group differences in long-term survival. RESULTS: Forty-four CHD patients were supported (age: median = 65 days, range = 4 days-13.3 years; weight [kg]: median = 4, range = 2.4-42.3). Ten biventricular CHD patients were supported with eight biventricular assist devices (BiVADs), one left ventricular assist device (LVAD) only, and one LVAD converted to BiVAD, while 34 univentricular CHD patients were supported with single ventricle-ventricular assist devices (sVADs). In CHD patients, duration of VAD support was [days]: median = 134, range = 4-554. Of 44 CHD patients, 28 underwent heart transplantation, 15 died on VAD, and one was still on VAD. Thirty-seven AHD patients were supported (age: median = 1.9 years, range = 27 days-17.7 years; weight [kg]: median = 11, range = 3.1-112), including 34 BiVAD and 3 LVAD. In AHD patients, duration of VAD support was [days]: median = 97, range = 4-315. Of 37 AHD patients, 28 underwent transplantation, three died on VAD, five weaned off VAD (one of whom underwent heart transplantation 334 days after weaning), and one was still on VAD. One-year survival after VAD insertion was 59.9% (95% CI = 46.7%-76.7%) in CHD and 88.6% (95% CI = 78.8%-99.8%) in AHD, P = .0004. Five-year survival after VAD insertion was 55.4% (95% CI = 40.8%-75.2%) in CHD and 85.3% (95% CI = 74.0%-98.2%) in AHD, P = .002. CONCLUSIONS: Pulsatile VAD facilitates bridge-to-transplantation in neonates, infants, and children with CHD; however, survival after VAD insertion is worse in patients with CHD than in patients with AHD.

Association of Olfaction and Microstructural Integrity of Brain Tissue in Community-Dwelling Adults: Atherosclerosis Risk in Communities Neurocognitive Study.

BACKGROUND AND OBJECTIVES: Research on olfaction and brain neuropathology may help understand brain regions associated with normal olfaction and dementia pathophysiology. To identify early regional brain structures affected in poor olfaction, we examined cross-sectional associations of microstructural integrity of the brain with olfaction in the Atherosclerosis Risk in Communities Neurocognitive Study. METHODS: Participants were selected from a prospective cohort study of community-dwelling adults; selection criteria included the following: evidence of cognitive impairment, participation in a previous MRI study, and a random sample of cognitively normal participants. Microstructural integrity was measured by 2 diffusion tensor imaging (DTI) measures, fractional anisotropy (FA) and mean diffusivity (MD), and olfaction by a 12-item odor identification test at the same visit. Higher FA and MD values indicate better and worse microstructural integrity, respectively, and higher odor identification scores indicate better olfaction. We used brain region-specific linear regression models to examine associations between DTI measures and olfaction, adjusting for potential confounders. RESULTS: Among 1,418 participants (mean age 76 ± 5 years, 41% male, 21% Black race, 59% with normal cognition), the mean olfaction score was 9 ± 2.3. Relevant to olfaction, higher MD in the medial temporal lobe (MTL) regions, namely the hippocampus (ß -0.79 [95% CI -0.94 to -0.65] units lower olfaction score per 1 SD higher MD), amygdala, entorhinal area, and some white matter (WM) tracts connecting to these regions, was associated with olfaction. We also observed associations with MD and WM FA in multiple atlas regions that were not previously implicated in olfaction. The associations between MD and olfaction were particularly stronger in the MTL regions among individuals with mild cognitive impairment (MCI) compared with those with normal cognition (e.g., ßhippocampus -0.75 [95% CI -1.02 to -0.49] and -0.44 [95% CI -0.63 to -0.26] for MCI and normal cognition, respectively, p interaction = 0.004). DISCUSSION: Neuronal microstructural integrity in multiple brain regions, particularly the MTL (the regions known to be affected in early Alzheimer disease), is associated with odor identification ability. Differential associations in the MTL regions among cognitively normal individuals compared with those with MCI may reflect the earlier vs later effects of the dementia pathogenesis. It is likely that some of the associated regions may not have any functional relevance to olfaction.

Association of Plasma Aß42/Aß40 Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the relationship between plasma ß-amyloid (Aß), specifically the ratio of 2 Aß peptides (the Aß42/Aß40 ratio, which correlates with increased accumulation of Aß in the CNS), and late-onset epilepsy (LOE). METHODS: We used Medicare fee-for-service claims codes from 1991 to 2018 to identify cases of LOE among 1,424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aß42/Aß40 ratio was calculated from plasma samples collected from ARIC participants in 1993-1995 (age 50-71 years) and 2011-2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aß42/Aß40, and its change from midlife to late life, and the subsequent development of epilepsy. We adjusted for demographics, the apolipoprotein e4 genotype, and comorbidities, including stroke, dementia, and head injury. A low plasma ratio of 2 Aß peptides, the Aß42/Aß40 ratio, correlates with low CSF Aß42/Aß40 and with increased accumulation of Aß in the CNS. RESULTS: Decrease in plasma Aß42/Aß40 ratio from midlife to late life, but not an isolated measurement of Aß42/Aß40, was associated with development of epilepsy in later life. For every 50% reduction in Aß42/Aß40, there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17). DISCUSSION: A reduction in plasma Aß42/Aß40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aß, hyperexcitable states, and LOE.