The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core: A culturally informed, community-engaged research (CI-CER) model to advance brain health equity.

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core was launched to advance Alzheimer's disease (AD) and AD-related dementia (ADRD) health equity research in underrepresented populations (URPs). We describe our evidence-based, scalable culturally informed, community-engaged research (CI-CER) model and demonstrate its preliminary success in increasing URP enrollment. METHODS: URPs include ethnoculturally minoritized, lower education (≤ 12 years), and rural populations. The CI-CER model includes: (1) culturally informed methodology (e.g., less restrictive inclusion/exclusion criteria, sociocultural measures, financial compensation, results disclosure, Spanish Language Capacity Workgroup) and (2) inclusive engagement methods (e.g., the Engagement Core team; Hub Sites; Community-Science Partnership Board). RESULTS: As of April 2024, 60% of ADNI-4 new in-clinic enrollees were from ethnoculturally or educationally URPs. This exceeds ADNI-4's ≥ 50% URP representation goal for new enrollees but may not represent final enrollment. DISCUSSION: Findings show a CI-CER model increases URP enrollment in AD/ADRD clinical research and has important implications for clinical trials to advance health equity. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) uses a culturally informed, community-engaged research (CI-CER) approach. The CI-CER approach is scalable and sustainable for broad, multisite implementation. ADNI-4 is currently exceeding its inclusion goals for underrepresented populations.

Centering the role of community health workers in social risk screening, referral, and follow-up within the primary care setting.

BACKGROUND: Community health workers (CHWs) remain an underutilized resource in social risk diagnostics in the primary care setting. This process evaluation study seeks to assess the role of CHWs in social risk screening, referral, and follow-up through process mapping to identify barriers to the process for future quality improvement efforts. METHODS: Researchers at the Arizona Prevention Research Center (AzPRC) engaged with two Federally Qualified Health Centers (FQHCs) in two of Arizona's major urban areas to evaluate their internal processes for social risk screening and intervention. The Consolidated Framework for Implementation Research (CFIR) was used to direct a process mapping exercise to visually describe the workflow, gaps, and barriers to identifying and addressing social risk. RESULTS: The process unveiled key areas for health system improvements in the community setting, the organizational setting, and in the implementation of social risk screening, referral, and follow-up. Further, process maps highlight the potential resources needed for effective CHW integration to address social risk in the primary care setting. CONCLUSIONS: Our findings demonstrate the importance of organizational tools, such as process mapping, to assist primary care settings in evaluating internal processes for quality improvement in addressing social risk and in effectively integrating the CHW workforce. Subsequent research will evaluate rates of social risk screening, referral, and follow-up within all of Arizona's FQHCs and propose models for CHW integration to address social risk in primary care and strengthen social risk screening reach and effectiveness.

Relationships of hematocrit concentration with dementia from a multiethnic population-based study.

OBJECTIVE: Red blood cell (RBC) concentration impacts cerebrovascular disease, yet it is unclear whether RBC concentrations relate to dementia risk, particularly in racially/ethnically diverse cohorts. We investigated whether RBC concentrations associate with incident dementia risk in a diverse population of stroke-free individuals and explored whether cerebral small vessel disease (CSVD) mediates this relationship. METHODS: A longitudinal observational analysis was performed using a population-based cohort of stroke-free, older adult participants (>50 years) from the Northern Manhattan Study (NOMAS) enrolled between 2003-2008. Participants received baseline hematocrit testing, MRI neuroimaging, and cognitive assessments at baseline and long-term follow-up. Associations of baseline hematocrit as a categorical variable (low, normal [reference], and high based on laboratory reference levels) with incident dementia were assessed using Cox models adjusting for relevant covariates. Separate analyses investigated whether MRI CSVD mediated these relationships. RESULTS: We studied 1207 NOMAS participants (mean age 71±9 years, 60% female, 66% Hispanic). Mean hematocrit was 41.2% (±3.8) with 16% of participants developing incident dementia. Lower hematocrit associated with increased dementia risk (adjusted hazard ratio 1.81 [1.01-3.23]) after adjusting for age, sex, race/ethnicity, education, APOE status, and comorbidities. High hematocrit was not associated with dementia risk. No interactions by sex or race/ethnicity were seen and baseline CSVD did not mediate relationships between hematocrit and dementia. CONCLUSIONS: Low hematocrit associated with dementia risk in our diverse population cohort. Further work is needed to assess mechanisms behind anemia's relationship with dementia to assess whether this can serve as a trackable, preventable/treatable risk factor for dementia.

Use of a decision support tool and quick start onboarding tool in individuals with type 1 diabetes using advanced automated insulin delivery: a single-arm multi-phase intervention study.

BACKGROUND: Multiple clinician adjustable parameters impact upon glycemia in people with type 1 diabetes (T1D) using Medtronic Mini Med 780G (MM780G) AHCL. These include glucose targets, carbohydrate ratios (CR), and active insulin time (AIT). Algorithm-based decision support advising upon potential settings adjustments may enhance clinical decision-making. METHODS: Single-arm, two-phase exploratory study developing decision support to commence and sustain AHCL. Participants commenced investigational MM780G, then 8 weeks Phase 1-initial optimization tool evaluation, involving algorithm-based decision support with weekly AIT and CR recommendations. Clinicians approved or rejected CR and AIT recommendations based on perceived safety per protocol. Co-design resulted in a refined algorithm evaluated in a further identically configured Phase 2. Phase 2 participants also transitioned to commercial MM780G following "Quick Start" (algorithm-derived tool determining initial AHCL settings using daily insulin dose and weight). We assessed efficacy, safety, and acceptability of decision support using glycemic metrics, and the proportion of accepted CR and AIT settings per phase. RESULTS: Fifty three participants commenced Phase 1 (mean age 24.4; Hba1c 61.5mmol/7.7%). The proportion of CR and AIT accepted by clinicians increased between Phases 1 and 2 respectively: CR 89.2% vs. 98.6%, p < 0.01; AIT 95.2% vs. 99.3%, p < 0.01. Between Phases, mean glucose percentage time < 3.9mmol (< 70mg/dl) reduced (2.1% vs. 1.4%, p = 0.04); change in mean TIR 3.9-10mmol/L (70-180mg/dl) was not statistically significant: 72.9% ± 7.8 and 73.5% ± 8.6. Quick start resulted in stable TIR, and glycemic metrics compared to international guidelines. CONCLUSION: The co-designed decision support tools were able to deliver safe and effective therapy. They can potentially reduce the burden of diabetes management related decision making for both health care practitioners and patients. TRIAL REGISTRATION: Prospectively registered with Australia/New Zealand Clinical Trials Registry(ANZCTR) on 30th March 2021 as study ACTRN12621000360819.

Brain artery diameters and risk of dementia and stroke.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Factors associated with having COVID-19 among unvaccinated pregnant and non-pregnant women in Metro Manila, Philippines: a multicentre longitudinal cohort study.

OBJECTIVE: To determine the potential risk factors associated with having COVID-19 among unvaccinated pregnant and non-pregnant women. DESIGN: A multicentre prospective cohort study among eligible women in Metro Manila, Philippines, from 2020 to 2022. SETTING: Five national and local hospital research sites altogether recruited and screened 500 consenting eligible individuals. PARTICIPANTS: Pregnant and non-pregnant participants meeting the eligibility criteria were admitted for a reverse-transcription PCR determination of SARS-CoV-2, pregnancy testing and ultrasound, and an interview with an administered questionnaire. EXPOSURES: Primary exposure was pregnancy; secondary exposures involve sociodemographic, lifestyle and obstetric-gynaecologic factors. OUTCOME MEASURE: Outcome being measured was COVID-19 status. RESULTS: The significant COVID-19 risk factors were: pregnancy (PR=1.184, 95% CI 1.096, 1.279), having a white-collar job (PR=1.123, 95% CI 1.02, 1.235), travelling abroad (PR=1.369, 95% CI 1.083, 1.173) and being infected by at least one vaccine-preventable disease (VPD) (PR=1.208, 95% CI 1.113, 1.310). Protective factors included having graduate-level education (PR=0.787, 95% CI 0.649, 0.954), immunisation against a VPD (PR=0.795, 95% CI 0.733, 0.862) and practising contraception (PR=0.889, 95% CI 0.824, 0.960). CONCLUSION: This study is the first in the country to determine the risks influencing COVID-19 infection among unvaccinated pregnant and non-pregnant women. Pregnancy is a significant risk for COVID-19 among women in Metro Manila. Educational attainment and positive health behaviours seem to confer protection. Occupations and activities that increase the frequency of interactions, as well as history of communicable diseases may predispose women to COVID-19. Further studies are needed to elucidate the development of the disease in pregnant women, including the maternal and neonatal effects of COVID-19 via potential vertical mechanisms of transmission.

The Longitudinal Effects of Blood Pressure and Hypertension on Neurocognitive Performance in People Living With HIV.

BACKGROUND: Hypertension (HTN) and HIV are salient risk factors for cerebral small vessel disease and neurocognitive (NC) impairment, yet the effects of HTN on NC performance in persons living with HIV remain poorly understood. This is the first study to examine the longitudinal associations between blood pressure (BP), HTN, and pulse pressure (PP) with NC performance in persons living with HIV. SETTING: New York City. METHODS: Analysis of medical, NC, and virologic data from 485 HIV+ participants was collected by the Manhattan HIV Brain Bank, a prospective, observational, longitudinal study of neuroHIV. A series of multilevel linear growth curve models with random intercepts and slopes were estimated for BP, HTN status, and PP to predict the change in NC performance. RESULTS: The baseline prevalence of HTN was 23%. Longitudinal changes in diastolic and systolic pressure were associated with a 10.5-second and 4-second increase in the Grooved Pegboard Test nondominant hand performance, respectively. A longitudinal change in diastolic BP was also associated with a 0.3-point decline in correct categories and 3-point increase in perseverative responses and total errors on the Wisconsin Card Sorting Test. Increasing odds of prevalent and/or incident HTN were associated with a 0.1-point decrease in correct categories and a 0.8-point increase in total errors on the Wisconsin Card Sorting Test. There was no association between PP and NC performance. CONCLUSIONS: The results indicate linear longitudinal relations for BP and HTN with poorer NC test performance, particularly in psychomotor and executive functions in persons with HIV.

The impact of sociocultural factors on prospective memory performance in HIV+ Latinx adults.

OBJECTIVE: Prospective memory (PM), a salient component of neurocognitive functioning for people living with HIV (PLH), is necessary for planning and coordinating health-related behaviors and instrumental tasks of daily living. However, little is known regarding the impact of sociocultural factors on PM in diverse populations, particularly Latinx PLH. The aim of this study was to examine ethnic group differences and sociocultural factors related to PM. METHOD: The sample of 127 PLH (91 Latinx and 36 non-Latinx white) completed measures of quality of education, socioeconomic status (SES), and a validated PM measure, the Memory for Intentions Screening Test (MIST). The Latinx group also completed a bicultural acculturation measure. RESULTS: Results revealed the Latinx and the non-Latinx white groups did not significantly differ in overall MIST performance (all p > .05). In the entire sample, better quality of education was associated with better MIST performance (all p < .05). Within the Latinx group, higher Latinx acculturation was associated with worse MIST performance (p = .02), whereas higher U.S. acculturation was associated with better MIST performance at a trend level (p = .07). Multivariate regressions revealed quality of education and Latinx acculturation significantly predicted MIST performance and PM errors (all p < .05). SES was not related to the MIST (all p > .10). CONCLUSIONS: In sum, clinicians must take sociocultural factors into consideration when working with Latinx PLH, as these factors influence cognitive functions (i.e., PM) vital to health-related behaviors. Integrating culturally-informed psychoeducation into care plans is an imperative first step. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cultural Neuropsychology Considerations in the Diagnosis of HIV-Associated Neurocognitive Disorders.

Human Immunodeficiency Virus Type-I (HIV) is a health disparities issue that affects culturally and linguistically diverse (CALD) and underrepresented minority populations to a greater degree than non-Hispanic white populations. Neurologically speaking, CALD populations experience worse HIV-related health outcomes, which are exacerbated by inadequate neurocognitive measures, poor normative samples, and the complex interplay of sociocultural factors that may affect test interpretation. Although cross-cultural neuropsychologists are working diligently to correct this gap in the literature, currently, studies examining neurocognitive outcomes among CALD populations are sparse. The most well-studied CALD groups are of African American/Black and Latinx adults in the US, and the chapter therefore focuses on these studies. There is more limited work among other populations in the US, such as Asians, Native Hawaiians, Pacific Islanders, and American Indians/Alaskan Natives, and even fewer studies for many CALD populations outside of the US. For example, HIV neuropsychology data is rare or nonexistent in the First Peoples of Australia and Indigenous People of Canada. It is often not adequately reported in Europe for the migrant populations within those countries or other world regions that have historically large multicultural populations (e.g., South America, Caribbean countries, Asia, and Africa). Therefore, this chapter reviews HIV-related health disparities faced by CALD populations with focus on North American research where it has been specifically studied, with particular attention given to disparities in HIV-Associated Neurocognitive Disorders (HAND). International data was also included for research with focus on First Peoples of Australia and Indigenous People of Canada. The chapter also examines other sociocultural and health factors, including global and regional (e.g., rural versus urban) considerations, migration, and gender. Further, guidelines for incorporating sociocultural consideration into assessment and interpretation of neurocognitive data and HAND diagnosis when working with HIV-positive CALD populations that would be relevant internationally are provided.

Depressive Symptoms Differentially Predict Neurocognition in Latinx and Non-Hispanic White People Living with HIV.

OBJECTIVES: Depression is common in people living with HIV (PLWH) and can contribute to neurocognitive dysfunction. Depressive symptoms in PLWH are often measured by assessing only cognitive/affective symptoms. Latinx adults, however, often express depressive symptoms in a somatic/functional manner, which is not typically captured in assessments of depression among PLWH. Given the disproportionate burden of HIV that Latinx adults face, examining whether variations in expressed depressive symptoms differentially predict neurocognitive outcomes between Latinx and non-Hispanic white PLWH is essential. METHODS: This cross-sectional study included 140 PLWH (71% Latinx; 72% male; mean (M) age = 47.1 ± 8.5 years; M education = 12.6 ± 2.9 years) who completed a comprehensive neurocognitive battery, Wechsler Test of Adult Reading (WTAR), and Beck Depression Inventory-II (BDI-II). Neurocognitive performance was measured using demographically adjusted T-scores. BDI-II domain scores were computed for the Fast-Screen (cognitive/affective items) score (BDI-FS) and non-FS score (BDI-NFS; somatic/functional items). RESULTS: Linear regressions revealed that the BDI-NFS significantly predicted global neurocognitive function and processing speed in the Latinx group (p < .05), such that higher physical/functional symptoms predicted worse performance. In the non-Hispanic white group, the cognitive/affective symptoms significantly predicted processing speed (p = .02), with more symptoms predicting better performance. Interaction terms of ethnicity and each BDI sub-score indicated that Latinx participants with higher cognitive/affective symptoms performed worse on executive functioning. CONCLUSIONS: Depressive symptoms differentially predict neurocognitive performance in Latinx and non-Hispanic white PLWH. These differences should be considered when conducting research and intervention among the increasingly culturally and ethnically diverse population of PLWH.

The neurocognitive effects of a past cannabis use disorder in a diverse sample of people living with HIV.

People living with HIV (PLWH) report higher rates of cannabis use than the general population, a trend likely to continue in light of recent policy changes and the reported therapeutic benefits of cannabis for PLWH. Therefore, it is important to better understand cannabis-associated effects on neurocognition, especially as PLWH are at heightened risk for neurocognitive impairment. This study aimed to elucidate the effects of a past cannabis use disorder on current neurocognition in a diverse sample of PLWH. This cross-sectional study included 138 PLWH (age M(SD) = 47.28(8.06); education M(SD) = 12.64(2.73); 73% Male; 71% Latinx) who underwent neuropsychological, DSM-diagnostic, and urine toxicology evaluations. One-way ANCOVAs were conducted to examine effects of a past cannabis use disorder (CUD+) on tests of attention/working memory, processing speed, executive functioning, verbal fluency, learning, memory, and motor ability. Compared to the past CUD- group, the past CUD+ group performed significantly better on tests of processing speed, visual learning and memory, and motor ability (p's < .05). Findings suggest PLWH with past cannabis use have similar or better neurocognition across domains compared to PLWH without past use.

Real-world insights from launching remote peer-to-peer mentoring in a safety net healthcare delivery setting.

Peer mentors have been proven to improve diabetes outcomes, especially among diverse patients. Delivering peer mentoring via remote strategies (phone, text, mobile applications) is critical, especially in light of the recent pandemic. We conducted a real-world evaluation of a remote diabetes intervention in a safety-net delivery system in New York. We summarized the uptake, content, and pre-post clinical effectiveness for English- and Spanish-speaking participants. Of patients who could be reached, 71% (n = 690/974) were enrolled, and 90% of those (n = 618/690) participated in coaching. Patients and mentors had a mean of 32 check-ins, and each patient set an average of 10 goals. 29% of the participants accessed the program via the smartphone application. Among participants with complete hemoglobin A1c data (n = 179), there was an absolute 1.71% reduction (P < .01). There are multiple lessons for successful implementation of remote peer coaching into settings serving diverse patients, including meaningful patient-mentor matching and addressing social determinants.

Disparities in Electronically Monitored Antiretroviral Adherence and Differential Adherence Predictors in Latinx and Non-Latinx White Persons Living with HIV.

Antiretroviral therapy (ART) adherence is vital for optimal HIV treatment. However, there is limited ART adherence research on the US Latinx population, who are at increased risk for HIV infection and worse HIV health outcomes. This study examined electronically measured ART adherence (Medication Event Monitoring System) and its association with demographic, clinical, neurocognitive, and sociocultural variables in Latinx and non-Latinx white (NLW) persons living with HIV [PLWH (N = 128)]. Latinx participants demonstrated worse adherence than NLW participants (p = 0.04). Linear regressions revealed different predictors of adherence. Among Latinx participants, recent cocaine use, stress, and, unexpectedly, higher US acculturation predicted worse adherence (ps < 0.05). Among NLW participants, recent cocaine use predicted worse adherence (p < 0.05). Intergroup comparisons within the Latinx group were not conducted due to subsample size. Thus, ethnicity, sociocultural variables, and cocaine use are important considerations for ART adherence, and poor ART adherence may be one pathway explaining worse outcomes in Latinx PLWH. Culturally tailored adherence interventions incorporating substance use treatment, acculturation, and stress management are warranted to improve health outcomes.

Update on hypoglossal nerve stimulation in children with down syndrome and obstructive sleep apnea.

OBJECTIVES/HYPOTHESIS: Hypoglossal nerve (HGN) stimulation is a novel therapy for obstructive sleep apnea (OSA) in adults. Its efficacy and safety in children with Down syndrome (DS) was previously reported in a preliminary case series of six adolescents. STUDY DESIGN: Case series. METHODS: Twenty nonobese children and adolescents (aged 10-21 years) with DS and severe OSA (apnea-hypopnea index [AHI] >10 and <50 events/hr) despite prior adenotonsillectomy were enrolled. Participants had failed a trial of continuous positive airway pressure therapy and underwent sleep endoscopy confirming surgical candidacy. The primary outcome was to assess safety and monitor for adverse events. Secondary outcomes included efficacy in reducing AHI (% reduction in AHI), adherence to therapy, and change in a validated quality-of-life instrument, the OSA-18 survey. RESULTS: All 20 children (median age = 16.0 years [interquartile range = 13-17 years], 13 male) were implanted with no long-term complications. We report two interval adverse events, both of which were corrected with revision surgery. Twenty participants completed the 2-month polysomnogram, with median percent reduction in titration AHI of 85% (interquartile range = 75%-92%). The median nightly usage for these children was 9.21 hours/night. There was a median change in the OSA-18 score of 1.15, indicating a moderate, yet significant, clinical change. CONCLUSIONS: HGN stimulation was safe and effective in the study population. Two minor surgical complications were corrected surgically. Overall, these data suggest that pediatric HGN stimulation appears to be a safe and effective therapy for children with DS and refractory severe OSA. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:E263-E267, 2020.

Brain arterial dilatation and the risk of Alzheimer's disease.

INTRODUCTION: We tested the hypothesis that brain arterial dilatation increases the risk of Alzheimer's dementia (AD). METHODS: We studied dementia-free participants in the Washington Heights-Inwood Columbia Aging Project who had a brain MRI and post-MRI dementia adjudication. We measured the axial T2-proton density diameters of the intracranial carotids and basilar diameters and used Cox models to obtain AD hazard ratios and 95% intervals. RESULTS: Of 953 participants (mean age 77 ± 7 y, women 64%, 71% nonwhite) followed on average for 3 ± 3 years, 76 (8%) developed AD. In a model adjusted for demographics, vascular risks, apolipoprotein E (APOE)-ε4, and white matter hyperintensities, larger carotid diameters increased the risk of AD, defined categorically as ≥ 90th percentile (HR 4.34, 1.70-11.11) or continuously (HR 1.44 per SD, 1.07-1.94). DISCUSSION: Understanding the pathophysiology of the association between AD and brain arterial dilatation may reveal new clues to the vascular contributions to AD.

Circulating inflammatory biomarkers are related to cerebrovascular disease in older adults.

Objective: This investigation aimed at examining whether circulating inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to cerebrovascular disease (CVD) assessed by MRI. Methods: The study included nondemented elderly participants of a community-based, multiethnic cohort, who received baseline MRI scans and had CRP (n = 508), ACT (435), and IL6 (N = 357) measured by ELISA. Silent brain infarcts and white matter hyperintensities (WMH) were derived from all available MRI scans at baseline, approximately 4.4 years after blood sample collection for inflammatory biomarkers. Repeated assessments of infarcts and WMH, as well as microbleeds assessment, were performed at follow-up MRI visits around 4.5 years later. Cross-sectional and longitudinal relationship between inflammatory biomarkers and CVD were analyzed using appropriate logistic regression models, generalized linear models, or COX models. Results: After adjusting for age, sex, ethnicity, education, APOE genotype, and intracranial volume, 1 SD increase in log10IL6 was associated with infarcts on MRI {odds ratio [OR] (95% confidence interval [CI]) = 1.28 [1.02-1.60], p = 0.033}, and 1 SD increase in log10CRP and log10ACT was associated with microbleeds (OR [95% CI] = 1.46 [1.02-2.09], p = 0.041; and 1.65 [1.11-2.46], p = 0.013; respectively). One SD increase in log10ACT was also associated with larger WMH at the follow-up MRI (b = 0.103, p = 0.012) and increased accumulation of WMH volume (b = 0.062, p = 0.041) during follow-up. The associations remained significant after additional adjustment of vascular risk factors and excluding participants with clinical stroke. Conclusions: Among older adults, increased circulating inflammatory biomarkers were associated with the presence of infarcts and microbleeds, WMH burden, and progression of WMH.

Perceptual Clinical Features in Exercise-Induced Laryngeal Obstruction (EILO): Toward Improved Diagnostic Approaches.

INTRODUCTION: Athletes with exercise-induced laryngeal obstruction (EILO) (previously commonly referred to as paradoxical vocal fold motion disorder, or paradoxical vocal fold motion, among other terms) are often misdiagnosed, resulting in prolonged, and at times inappropriate, clinical management. The high prevalence of misdiagnosis is largely due to a lack of universal consensus of key clinical features indicating EILO and a dearth of validated quantitative approaches to accurately detect episodic laryngeal breathing disorders (ELBD) from other pathologies. Additionally, mechanisms underlying EILO clinical presentation are poorly understood, further confounding identification and management of the condition. Therefore, the objectives of this study were twofold. The first was to identify patient-centered perception of symptoms that could distinguish adolescent athletes with EILO from athletes without the condition, at baseline (rest) and during an exercise challenge (provocation), and to quantify symptom severities for use as preliminary diagnostic benchmarks. The second objective was to investigate the merit of one commonly proposed mechanism in the EILO literature-stress reactivity (temperament)-by comparing personality traits in athletes with and without EILO. METHODS: Twelve (12) athletes diagnosed with EILO and 14 healthy athletic volunteers without the condition were asked to rate the severity of their present symptoms using a 0-100 continuous visual analog scale. Participants then underwent an exercise challenge with simultaneous laryngoscopy and were asked to complete the same set of symptom severity ratings experienced during rigorous exercise. Finally, participants completed the Fear subscale on the early adolescent temperament questionnaire-revised (EATQ-R) to measure self-perceived levels of stress reactivity. RESULTS: There were significant group differences for inspiratory and expiratory dyspnea with exercise (P = 0.01). Symptoms of stridor (EILO: P = .01; control: P = .001) and throat tightness (EILO: P = .01, control: P = .01) were statistically different between rest and exercise in both groups. However, no group differences were found on these two parameters (P > .05). Other symptoms from the list of previously purported symptoms indicative of ELBD (e.g. cough, dysphonia) were infrequently reported in the exercise variant. Additionally, measurements of stress reactivity on the EATQ-R Fear subscale were similar between the two athletic groups. Interestingly, EATQ-R Fear Subscale scores for both groups were significantly higher compared to typical adolescents in the U.S. population (P < .001, respectively). DISCUSSION: Results suggest dyspnea severity, particularly when experienced during an exercise-induced ELBD (EILO) episode, is the most sensitive symptom parameter to distinguish individuals with EILO from those without the condition. These findings confirm previous literature describing episodic laryngeal breathing disorders in clinical cohorts. Results also showed symptoms of throat tightness and stridor is more prevalent during exercise, compared to rest. However, the level of their severity occurred variably across both groups of athletes and may point to a less robust indication of pathology. Finally, similarities to stress reactivity between the two athletic groups imply certain temperaments historically attributed to patients with EILO may instead better reflect temperaments in competitive young athletes, in general. CONCLUSION: Study findings highlight the importance of using normative comparisons in the study of episodic laryngeal breathing disorders to prevent overgeneralization of characteristics to clinical cohorts. Results also speak of the clinical utility of exercise challenge to improve specificity of EILO diagnosis.

Recessive Host Range Mutants and Unsusceptible Cells That Inactivate Virions without Genome Penetration: Ecological and Technical Implications.

Although microviruses do not possess a visible tail structure, one vertex rearranges after interacting with host lipopolysaccharides. Most examinations of host range, eclipse, and penetration were conducted before this "host-induced" unique vertex was discovered and before DNA sequencing became routine. Consequently, structure-function relationships dictating host range remain undefined. Biochemical and genetic analyses were conducted with two closely related microviruses, α3 and ST-1. Despite ∼90% amino acid identity, the natural host of α3 is Escherichia coli C, whereas ST-1 is a K-12-specific phage. Virions attached and eclipsed to both native and unsusceptible hosts; however, they breached only the native host's cell wall. This suggests that unsusceptible host-phage interactions promote off-pathway reactions that can inactivate viruses without penetration. This phenomenon may have broader ecological implications. To determine which structural proteins conferred host range specificity, chimeric virions were generated by individually interchanging the coat, spike, or DNA pilot proteins. Interchanging the coat protein switched host range. However, host range expansion could be conferred by single point mutations in the coat protein. The expansion phenotype was recessive: genetically mutant progeny from coinfected cells did not display the phenotype. Thus, mutant isolation required populations generated in environments with low multiplicities of infection (MOI), a phenomenon that may have impacted past host range studies in both prokaryotic and eukaryotic systems. The resulting genetic and structural data were consistent enough that host range expansion could be predicted, broadening the classical definition of antireceptors to include interfaces between protein complexes within the capsid.IMPORTANCE To expand host range, viruses must interact with unsusceptible host cell surfaces, which could be detrimental. As observed in this study, virions were inactivated without genome penetration. This may be advantageous to potential new hosts, culling the viral population from which an expanded host range mutant could emerge. When identified, altered host range mutations were recessive. Accordingly, isolation required populations generated in low-MOI environments. However, in laboratory settings, viral propagation includes high-MOI conditions. Typically, infected cultures incubate until all cells produce progeny. Thus, coinfections dominate later replication cycles, masking recessive host range expansion phenotypes. This may have impacted similar studies with other viruses. Last, structural and genetic data could be used to predict site-directed mutant phenotypes, which may broaden the classic antireceptor definition to include interfaces between capsid complexes.

White Matter Regions With Low Microstructure in Young Adults Spatially Coincide With White Matter Hyperintensities in Older Adults.

Microstructural and macrostructural white matter damage occurs frequently with aging, is associated with negative health outcomes, and can be imaged non-invasively as fractional anisotropy (FA) and white matter hyperintensities (WMH), respectively. The extent to which diminished microstructure precedes or results from macrostructural white matter damage is poorly understood. This study evaluated the hypothesis that white matter areas with normatively lower microstructure in young adults are most susceptible to develop WMH in older adults. Forty-nine younger participants (age = 25.8 ± 2.8 years) underwent diffusion-weighted imaging (DWI), and 557 older participants (age = 73.9 ± 5.7 years) underwent DWI and T2-weighted magnetic resonance imaging (MRI). In older adults, WMH had a mostly periventricular distribution with higher frequency in frontal regions. We found lower FA in areas of frank WMH compared to normal-appearing white matter (NAWM) in older adults. Then, to determine if areas of normatively lower white matter microstructure spatially overlap with areas that frequently develop macrostructural damage in older age, we created a WMH frequency map in which each voxel represented the percentage of older adults with a WMH in that voxel. We found lower normative FA in young adults with regions frequently segmented as WMH in older adults. We conclude that low white matter microstructure is observed in areas of white matter macrostructural damage, but white matter microstructure is also normatively low (i.e., at ages 20-30) in regions with high WMH frequency, prior to white matter macrostructural damage.