The Relationship of Fatigue, Pain Interference and Physical Disability in Children Newly Diagnosed with Juvenile Idiopathic Arthritis.

OBJECTIVES: Our objectives were to quantify the relationships between fatigue, pain interference and physical disability in children with JIA, and test whether fatigue mediates the relationship between pain interference and physical disability in JIA. METHODS: Patients enrolled within 3 months of JIA diagnosis in the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry between February 2017 and May 2023 were included. Their parents completed the PROMIS fatigue and pain interference short proxy questionnaires, and the CHAQ disability index at registry enrollment. Associations were assessed using Pearson's correlations and multiple linear regression. Structural equation modeling (SEM) was used to test if fatigue mediates the relationship between pain interference and physical disability. RESULTS: Among 855 patients (61.4% female, 44.1% with oligoarthritis), most reported fatigue and pain interference scores similar to the reference population, but 15.6% reported severe fatigue and 7.3% reported severe pain interference with wide variation across JIA categories. Fatigue was strongly correlated with pain interference (r = 0.72, p < 0.001) and with physical disability (r = 0.60, p < 0.001). Pain interference (b = 0.027, p < .001) and fatigue (b = 0.013, p < 0.001) were both associated with physical disability after controlling for each other and potential confounders. SEM supported our hypothesis that fatigue partially mediates the relationship between pain interference and physical disability. CONCLUSION: Our findings suggest both fatigue and pain interference are independently associated with physical disability in children newly diagnosed with JIA, and the effect of pain interference may be partly mediated by fatigue.

Peripheral hearing loss at age 70 predicts brain atrophy and associated cognitive change.

BACKGROUND: Hearing loss has been proposed as a modifiable risk factor for dementia. However, the relationship between hearing, neurodegeneration, and cognitive change, and the extent to which pathological processes such as Alzheimer's disease and cerebrovascular disease influence these relationships, is unclear. METHODS: Data from 287 adults born in the same week of 1946 who underwent baseline pure tone audiometry (mean age=70.6 years) and two time point cognitive assessment/multimodal brain imaging (mean interval 2.4 years) were analysed. Hearing impairment at baseline was defined as a pure tone average of greater than 25 decibels in the best hearing ear. Rates of change for whole brain, hippocampal and ventricle volume were estimated from structural MRI using the Boundary Shift Integral. Cognition was assessed using the Pre-clinical Alzheimer's Cognitive Composite. Regression models were performed to evaluate how baseline hearing impairment associated with subsequent brain atrophy and cognitive decline after adjustment for a range of confounders including baseline ß-amyloid deposition and white matter hyperintensity volume. RESULTS: 111 out of 287 participants had hearing impairment. Compared with those with preserved hearing, hearing impaired individuals had faster rates of whole brain atrophy, and worse hearing (higher pure tone average) predicted faster rates of hippocampal atrophy. In participants with hearing impairment, faster rates of whole brain atrophy predicted greater cognitive change. All observed relationships were independent of ß-amyloid deposition and white matter hyperintensity volume. CONCLUSIONS: Hearing loss may influence dementia risk via pathways distinct from those typically implicated in Alzheimer's and cerebrovascular disease in cognitively unimpaired older adults.

Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

The "Strong Black Woman" Paradox: Insights from a Cohort of Black Breast and Ovarian Cancer Patients and Family Members.

BACKGROUND: The strong Black woman (SBW) stereotype can be seen as a positive view of Black women and even a standard to uphold. SBW internalization is a coping mechanism for dealing with racism and sexism. However, multiple recent studies have indicated that Black women in the modern era experience the paradox of SBW internalization having negative generational health effects. We interviewed Black women with a personal or relation diagnosis of breast or ovarian cancer to understand their views and experiences, including how the perception of the SBW stereotype influenced their care. METHODS: Qualitative semi-structured interviews were conducted via telephone or video conference and transcribed verbatim. Transcripts were qualitatively analyzed for iterative themes related to cancer care and psychosocial support. RESULTS: Sixty-one Black women completed an interview. Responses in multiple transcripts expressed experiences and sentiments consistent with the SBW stereotype, including the importance of maintaining the appearance of strength during their cancer journey. This resulted in some patients declining assistance during their cancer journeys. Participants shared a hope that there would be more willingness to show vulnerability so that future generations of cancer patients receive adequate support. Key aspects of the SBW stereotype were also cited as potential contributors to ongoing racial disparities in breast and ovarian cancer outcomes. CONCLUSION(S): Participants described a paradox of the SBW stereotype that is ultimately detrimental to health and wellbeing. Healthcare professionals and cancer researchers should be aware of this phenomenon to address cancer care more appropriately in Black women.

Comparison of quantification methods for an endoscope lumen biofilm model.

Biofilm has been implicated in multi-drug resistant organism outbreaks following endoscopic procedures. Automated Endoscope Reprocessors (AER) are devices validated to clean and disinfect endoscopes per applicable standards. The ISO 15883 part 4 standard guides performance testing validation of AERs, including cleaning performance using a biofilm test soil. The standard recommends assessment of biofilm reduction using protein or carbohydrate quantification methods. The aim of this study was to assess the suitability of various quantification methods using the ISO biofilm model. The ISO 15883 part 5 biofilm test soil method was used to grow biofilm within lumens representative of endoscopes channels. The biofilm was then quantified using five methods: Crystal Violet (CV), Colony Forming Units (CFU), Total Organic Carbon (TOC), protein assay with Orthophtalaldehyde (OPA), and protein assay by micro bicinchoninic acid (µBCA). The five methods were statistically analyzed for their ability to assess biofilm reduction on samples accurately and precisely. In addition, the quantification methods were compared to demonstrate statistical equivalency, and thus their suitability for assessing biofilm cleaning performance testing of AERs.

Dose delivery reproducibility for PBS proton treatment of breast cancer patients with and without mask immobilization.

BACKGROUND: Setup reproducibility of the tissue in the proton beam path is critical in maintaining the planned clinical target volume (CTV) dose coverage and sparing the organs at risk (OAR). In this study, we retrospectively evaluated radiation therapy dose reproducibility for proton pencil beam scanning (PBS) treatment of breast cancer patients with and without mask immobilization. METHODS: Ninety-four patients treated between January 2019 and September 2022 with at least one verification CT scan (V-CT) in treatment position were included for this study. All patients were set up with arms up using the Orfit AIO patient positioning system, with (69 patients) or without (25 patients) mask immobilization in chin, neck, shoulder, upper arm, and chest areas. Two to three enface or near enface single field uniform dose PBS beams were optimized using a commercial treatment planning system. Prescription doses were 25 to 60 GyRBE in 5 to 45 fractions. Treatment plan doses re-calculated on V-CTs were compared to the corresponding planned doses. Cumulative doses were also calculated for patients with at least 3 V-CTs by deform and weighted sum doses from V-CTs to corresponding P-CTs. CTV D95%, ipsilateral-lung V40%, esophagus D0.01cc, and heart mean dose were evaluated and reported as percentages of prescription doses. Differences were large dose deteriorations (LDD) if: (1) CTV (V-CT/cumulative D95%) - (Planned D95%) < - 5%; or (2) Ipsilateral-lung (V-CT/cumulative V40%) - (Planned V40%) > 5%; or (3) Esophagus (V-CT/cumulative D0.01cc) - (Planned D0.01cc) > 10%; or (4) Heart (V-CT/cumulative mean) - (Planned mean) > 1.5%. RESULTS: On average, V-CT/cumulative and planned CTV/OAR dose parameter differences were less than 2.2%/1.7% and 3.4%/3.7% for masked and maskless patients, respectively. The percentages of patients with at least one CTV or OAR V-CT/cumulative dose LDD were 20.3%/25.0% and 72.0%/54.0% for masked and maskless patients, respectively. CONCLUSIONS: On average, masked/maskless setups achieved delivered and planned CTV/OAR dose parameters agreed within 2.2%/3.7% for PBS treatment of breast cancer patients in this study. Maskless patients had higher rate of CTV/OAR LDDs compared to masked patients. Dosimetric differences large enough to raise clinical concerns in either group were able to be addressed with replannings.

Neuroimaging, clinical and life course correlates of normal-appearing white matter integrity in 70-year-olds.

We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI. Linear regression was used to test associations between normal-appearing white matter metrics and (i) concurrent measures, including whole brain volume, white matter hyperintensity volume, PET amyloid and cognition; (ii) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socio-economic position and genetic risk for Alzheimer's disease (APOE-ɛ4); (iii) systolic and diastolic blood pressure and cardiovascular health (Framingham Heart Study Cardiovascular Risk Score) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). Three hundred and sixty-two participants met inclusion criteria (mean age 70, 49% female). Higher white matter hyperintensity volume was associated with lower fractional anisotropy [b = -0.09 (95% confidence interval: -0.11, -0.06), P < 0.01], neurite density index [b = -0.17 (-0.22, -0.12), P < 0.01] and higher mean diffusivity [b = 0.14 (-0.10, -0.17), P < 0.01]; amyloid (in men) was associated with lower fractional anisotropy [b = -0.04 (-0.08, -0.01), P = 0.03)] and higher mean diffusivity [b = 0.06 (0.01, 0.11), P = 0.02]. Framingham Heart Study Cardiovascular Risk Score in later-life (age 69) was associated with normal-appearing white matter {lower fractional anisotropy [b = -0.06 (-0.09, -0.02) P < 0.01], neurite density index [b = -0.10 (-0.17, -0.03), P < 0.01] and higher mean diffusivity [b = 0.09 (0.04, 0.14), P < 0.01]}. Significant sex interactions (P < 0.05) emerged for midlife cardiovascular health (age 53) and normal-appearing white matter at 70: marginal effect plots demonstrated, in women only, normal-appearing white matter was associated with higher midlife Framingham Heart Study Cardiovascular Risk Score (lower fractional anisotropy and neurite density index), midlife systolic (lower fractional anisotropy, neurite density index and higher mean diffusivity) and diastolic (lower fractional anisotropy and neurite density index) blood pressure and greater blood pressure change between 43 and 53 years (lower fractional anisotropy and neurite density index), independently of white matter hyperintensity volume. In summary, poorer normal-appearing white matter microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how normal-appearing white matter can provide additional information to overt white matter disease. Our findings further show that greater 'midlife' cardiovascular risk and higher blood pressure were associated with poorer normal-appearing white matter microstructural integrity in females only, suggesting that women's brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health.

Naringenin and ß-carotene convert human white adipocytes to a beige phenotype and elevate hormone- stimulated lipolysis.

Introduction: Naringenin, a peroxisome proliferator-activated receptor (PPAR) activator found in citrus fruits, upregulates markers of thermogenesis and insulin sensitivity in human adipose tissue. Our pharmacokinetics clinical trial demonstrated that naringenin is safe and bioavailable, and our case report showed that naringenin causes weight loss and improves insulin sensitivity. PPARs form heterodimers with retinoic-X-receptors (RXRs) at promoter elements of target genes. Retinoic acid is an RXR ligand metabolized from dietary carotenoids. The carotenoid ß-carotene reduces adiposity and insulin resistance in clinical trials. Our goal was to examine if carotenoids strengthen the beneficial effects of naringenin on human adipocyte metabolism. Methods: Human preadipocytes from donors with obesity were differentiated in culture and treated with 8µM naringenin + 2µM ß-carotene (NRBC) for seven days. Candidate genes involved in thermogenesis and glucose metabolism were measured as well as hormone-stimulated lipolysis. Results: We found that ß-carotene acts synergistically with naringenin to boost UCP1 and glucose metabolism genes including GLUT4 and adiponectin, compared to naringenin alone. Protein levels of PPARα, PPARγ and PPARγ-coactivator-1α, key modulators of thermogenesis and insulin sensitivity, were also upregulated after treatment with NRBC. Transcriptome sequencing was conducted and the bioinformatics analyses of the data revealed that NRBC induced enzymes for several non-UCP1 pathways for energy expenditure including triglyceride cycling, creatine kinases, and Peptidase M20 Domain Containing 1 (PM20D1). A comprehensive analysis of changes in receptor expression showed that NRBC upregulated eight receptors that have been linked to lipolysis or thermogenesis including the ß1-adrenergic receptor and the parathyroid hormone receptor. NRBC increased levels of triglyceride lipases and agonist-stimulated lipolysis in adipocytes. We observed that expression of RXRγ, an isoform of unknown function, was induced ten-fold after treatment with NRBC. We show that RXRγ is a coactivator bound to the immunoprecipitated PPARγ protein complex from white and beige human adipocytes. Discussion: There is a need for obesity treatments that can be administered long-term without side effects. NRBC increases the abundance and lipolytic response of multiple receptors for hormones released after exercise and cold exposure. Lipolysis provides the fuel for thermogenesis, and these observations suggest that NRBC has therapeutic potential.

Cancer Screening Experiences of Black Breast and Ovarian Cancer Patients and Family Members.

Black women experience disproportionate rates of advanced breast cancer diagnoses and mortality. Mammography is a proven and effective tool in early breast cancer detection and impacts patient outcomes. We interviewed Black women with a personal or family history of breast and/or ovarian cancer to understand their screening experiences and views. N = 61 individuals completed an interview. Interview transcripts were qualitatively analyzed for themes regarding clinical experiences, guideline adherence, and family sharing specific to Black women and their families. Most participants were college educated with active health insurance. Women in this cohort were knowledgeable about the benefits of mammography and described few barriers to adhering to annual mammogram guidelines. Some with first-degree family history were frustrated at insurance barriers to mammography before the age of 40. Participants were generally comfortable encouraging family and friends to receive mammograms and expressed a desire for a similar screening tool for ovarian cancer. However, they expressed concern that factors such as screening awareness and education, lack of insurance coverage, and other systematic barriers might prevent other Black women from receiving regular screening. Black women in this cohort reported high adherence to mammography guidelines, but expressed concern about cultural and financial barriers that may impact cancer screening access in the population more generally and contribute to disparities. Participants noted the importance of frank and open discussions of breast cancer screening in their families and community as a means of improving awareness.

"Scaling out" evidence-informed antenatal care to support healthy pregnancy weight gain: a context assessment using the Consolidated Framework for Implementation Research.

INTRODUCTION AND AIMS: Excess gestational weight gain is a challenge within antenatal care. Low-intensity interventions that offer opportunities for individualization, such as pregnancy weight-gain charts (PWGCs) combined with brief advice, have been a promising strategy but scaling out such interventions requires planning. The aim of this study was to examine current practices and conduct a context assessment using the Consolidated Framework for Implementation Research (CFIR) to guide implementation of PWGCs and brief intervention advice to support healthy pregnancy weight gain in two hospitals that provide antenatal care. METHODS: Retrospective chart audits and surveys of staff and women were used to understand current practice as well as barriers and enablers to implementing change according to the domains and constructs reported in the CFIR. RESULTS: Forty-eight percent (site A) and 46% (site B) of pregnant women who were audited ( n  = 180, site A; n  = 176, site B) gained weight above recommendations. Most women were unable to accurately report their recommended weight gain for pregnancy (93% site A, 94% site B). Although more than 50% of women reported discussions about weight gain during pregnancy, advice about physical activity and healthy eating (in the context of helping women to achieve healthy gestational weight gain) was low. Mapping barriers and enablers to the CFIR helped guide the selection of implementation strategies, including audit and feedback, informing local opinion leaders, obtaining consensus, identifying champions, and building a coalition. CONCLUSION: Scaling out of interventions can be enhanced by undertaking a detailed context assessment guided by implementation frameworks.

A comprehensive assessment of age at menopause with well-characterized cognition at 70 years: A population-based British birth cohort.

OBJECTIVES: Associations between age at menopause and cognition post-menopause are examined to determine whether relationships are stronger for certain cognitive domains. STUDY DESIGN: Women from the Medical Research Council National Survey of Health and Development and its neuroscience sub-study, Insight 46, were included if they had known age at menopause (self-reported via questionnaire) and complete cognitive outcome data at age 69 (n = 746) or at Insight 46 wave I (n = 197). Multivariable linear regression analyses adjusting for life course confounders were run; interactions with menopause type (natural/surgical) and APOE-ε4 status were examined; and the potential contribution of hormone therapy was assessed. MAIN OUTCOME MEASURES: Cognitive measures were standardized Addenbrooke's Cognitive Examination - third edition total and sub-domain scores at age 69 (whole cohort) and Preclinical Alzheimer's Cognitive Composite total and sub-test scores at age ~70 (Insight 46). RESULTS: Older age at menopause was associated with better performance across all outcomes, most strongly for the Addenbrooke's Cognitive Examination memory and visuospatial function sub-domains, and the Preclinical Alzheimer's Cognitive Composite digit-symbol substitution test and face-name associative memory examination sub-tests. Adjusting for early-life factors attenuated all effect estimates, driven by childhood cognition, and accounting for menopause type revealed negative confounding for some outcomes. No significant interactions with menopause type or APOE-ε4 status were detected. Further adjustment for hormone therapy did not meaningfully alter the estimated effects. CONCLUSIONS: Older age at menopause is associated with better later-life cognitive performance, particularly for visual processing and associative learning and memory domains. Childhood cognition was an important contributor.

Effects of Caffeine and Glucose Supplementation at Birth on Piglet Pre-Weaning Growth, Thermoregulation, and Survival.

Piglet pre-weaning mortality of approximately 15% represents a major economic and welfare concern to the pork industry. Supplementing neonatal piglets with glucose and/or caffeine has the potential to counteract hypoxic stress experienced during parturition and provide an energy substrate, which may improve survival to weaning. This study investigated the effects of caffeine and glucose supplementation at birth, in combination or separately, on piglet growth, thermoregulatory ability, and pre-weaning survival. At birth, 398 piglets were assigned to one of four oral treatments: saline, glucose (300 mg), caffeine (30 mg), or caffeine and glucose combined (30 mg caffeine and 300 mg glucose), dissolved in 6 mL saline. Piglets were tagged at birth, and time taken to reach the udder was recorded. Rectal temperatures were recorded at 4 h and 24 h post-partum, and body weights recorded at birth and 1, 3, and 18 days of age. Colostrum intake was estimated using birth and day 1 weights, and all pre-weaning mortalities were recorded. Treatments did not affect rectal temperature, colostrum intake, or pre-weaning mortality (p > 0.05). Low birth weight piglets (<0.9 kg) treated with caffeine and glucose had increased growth between 1 and 3 days of age (p < 0.05) compared to low birth weight piglets of other treatment groups. Caffeine supplementation alone reduced overall pre-weaning growth in low birth weight piglets compared to all other treatments (p = 0.05). Oral caffeine and glucose had no significant effect on piglet performance except in low birthweight piglets, where it improved growth in the first 3 days of life. Caffeine and glucose supplementation in combination may be beneficial for low birth weight piglets.

School start time delays and high school educational outcomes: Evidence from the START/LEARN study.

INTRODUCTION: Delaying high school start times extends adolescents' nightly sleep, but it is less clear how it affects educational outcomes. We expect links between school start time delays and academic performance because getting enough sleep is a key input to the cognitive, health, and behavioral factors necessary for educational success. Thus, we evaluated how educational outcomes changed in the 2 years following a school start time delay. METHODS: We analyzed 2153 adolescents (51% male, 49% female; mean age 15 at baseline) from START/LEARN, a cohort study of high school students in the Minneapolis-St. Paul, MN, USA metropolitan area. Adolescents experienced either a school start time delay ("policy change schools") or consistently early school start times ("comparison schools"). We compared patterns of late arrivals, absences, behavior referrals, and grade point average (GPA) 1 year before (baseline, 2015-2016) and 2 years after (follow-up 1, 2016-2017 and follow-up 2, 2017-2018) the policy change using a difference-in-differences analysis. RESULTS: A school start time delay of 50-65 min led to three fewer late arrivals, one fewer absence, a 14% lower probability of behavior referral, and 0.07-0.17 higher GPA in policy change schools versus comparison schools. Effects were larger in the 2nd year of follow-up than in the 1st year of follow-up, and differences in absences and GPA emerged in the second year of follow-up only. CONCLUSIONS: Delaying high school start times is a promising policy intervention not only for improving sleep and health but for improving adolescents' performance in school.

Investigating associations between blood metabolites, later life brain imaging measures, and genetic risk for Alzheimer's disease.

BACKGROUND: Identifying blood-based signatures of brain health and preclinical pathology may offer insights into early disease mechanisms and highlight avenues for intervention. Here, we systematically profiled associations between blood metabolites and whole-brain volume, hippocampal volume, and amyloid-ß status among participants of Insight 46-the neuroscience sub-study of the National Survey of Health and Development (NSHD). We additionally explored whether key metabolites were associated with polygenic risk for Alzheimer's disease (AD). METHODS: Following quality control, levels of 1019 metabolites-detected with liquid chromatography-mass spectrometry-were available for 1740 participants at age 60-64. Metabolite data were subsequently clustered into modules of co-expressed metabolites using weighted coexpression network analysis. Accompanying MRI and amyloid-PET imaging data were present for 437 participants (age 69-71). Regression analyses tested relationships between metabolite measures-modules and hub metabolites-and imaging outcomes. Hub metabolites were defined as metabolites that were highly connected within significant (pFDR < 0.05) modules or were identified as a hub in a previous analysis on cognitive function in the same cohort. Regression models included adjustments for age, sex, APOE genotype, lipid medication use, childhood cognitive ability, and social factors. Finally, associations were tested between AD polygenic risk scores (PRS), including and excluding the APOE region, and metabolites and modules that significantly associated (pFDR < 0.05) with an imaging outcome (N = 1638). RESULTS: In the fully adjusted model, three lipid modules were associated with a brain volume measure (pFDR < 0.05): one enriched in sphingolipids (hippocampal volume: ß = 0.14, 95% CI = [0.055,0.23]), one in several fatty acid pathways (whole-brain volume: ß = - 0.072, 95%CI = [- 0.12, - 0.026]), and another in diacylglycerols and phosphatidylethanolamines (whole-brain volume: ß = - 0.066, 95% CI = [- 0.11, - 0.020]). Twenty-two hub metabolites were associated (pFDR < 0.05) with an imaging outcome (whole-brain volume: 22; hippocampal volume: 4). Some nominal associations were reported for amyloid-ß, and with an AD PRS in our genetic analysis, but none survived multiple testing correction. CONCLUSIONS: Our findings highlight key metabolites, with functions in membrane integrity and cell signalling, that associated with structural brain measures in later life. Future research should focus on replicating this work and interrogating causality.

Timing of physical activity across adulthood on later-life cognition: 30 years follow-up in the 1946 British birth cohort.

BACKGROUND: To assess how timing, frequency and maintenance of being physically active, spanning over 30 years in adulthood, is associated with later-life cognitive function. METHODS: Participants (n=1417, 53% female) were from the prospective longitudinal cohort study, 1946 British birth cohort. Participation in leisure time physical activity was reported five times between ages 36 and 69, categorised into: not active (no participation in physical activity/month); moderately active (participated 1-4 times/month); most active (participated 5 or more times/month). Cognition at age 69 was assessed by tests of cognitive state (Addenbrooke's Cognitive Examination-III), verbal memory (word learning test) and processing speed (visual search speed). RESULTS: Being physically active, at all assessments in adulthood, was associated with higher cognition at age 69. For cognitive state and verbal memory, the effect sizes were similar across all adult ages, and between those who were moderately and most physically active. The strongest association was between sustained cumulative physical activity and later-life cognitive state, in a dose-response manner. Adjusting for childhood cognition, childhood socioeconomic position and education largely attenuated these associations but results mainly remained significant at the 5% level. CONCLUSIONS: Being physically active at any time in adulthood, and to any extent, is linked with higher later-life cognitive state, but lifelong maintenance of physical activity was most optimal. These relationships were partly explained by childhood cognition and education, but independent of cardiovascular and mental health and APOE-E4, suggestive of the importance of education on the lifelong impacts of physical activity.

"There's not enough studies": Views of black breast and ovarian cancer patients on research participation.

BACKGROUND: Black breast and ovarian cancer patients are underrepresented in clinical cancer trials disproportionate to the prevalence of these cancers in Black females. Historically, lower enrollment has been attributed to individualized factors, including medical mistrust, but more recently structural factors, including systemic racism, have received additional scrutiny. We interviewed Black women with a personal or family history of breast and ovarian cancer to understand their views and experiences related to research participation. METHODS: Qualitative interviews were conducted via telephone or video conference and transcribed verbatim. Transcripts were qualitatively analyzed for iterative themes related to the offer and participation in cancer clinical trials and research studies, impact on cancer care, and recommendations to increase enrollment of Black patients. RESULTS: Sixty-one Black women completed an interview. Participants expressed that Black women are underrepresented in cancer research, and that this negatively impacted their own care. Many cited past historical abuses, including the Tuskegee syphilis trial, as a potential factor for lower enrollment but suggested that lower enrollment was better understood in the context of the entirety of their healthcare experiences, including present-day examples of patient mistreatment or dismissal. Participants suggested that proactive community engagement, transparency, and increased representation of Black research team members were strategies likely to foster trust and bolster research participation. CONCLUSION(S): Medical mistrust is only a partial factor in the lower participation of Black patients in cancer research. Researchers should implement the strategies identified by our participants to promote diverse enrollment and ensure that Black patients are included in future therapeutic advances.

The effect of age on injury patterns in pedestrian deaths.

Although it is known that elderly pedestrians are at increased risk of injury and death from vehicle crashes the specific pattern of lethal injuries related to age has not been extensively studied. Data on the numbers of pedestrian fatalities and ages were obtained from 1990 to 2020 from the Traffic Accident Reporting System, The University of Adelaide, Adelaide, South Australia and detailed autopsy data on fatal pedestrian crashes from the pathology database at Forensic Science SA, Adelaide, South Australia from 2000 to 2020. Fatal injuries were separated into the following regions: head/face, spine, chest, abdomen and limbs/skeleton. Analysis of 634 cases of pedestrian fatalities (1990-2020) showed a significant decline in numbers over the years (p < 0.001). Analysis of fatal injuries in 219 cases (2000-2020) showed a significant reduction in the proportion of fatal head injuries with increasing age (p < 0.05), a significant increase in the proportion of fatal chest injuries with increasing age (p < 0.01) and a significant increase in the proportion of fatal limb/skeletal injuries with increasing age (p < 0.05). Older pedestrians are, therefore, more likely to sustain lethal chest and limb/skeletal injuries than head injuries compared to those who are younger, presumably due to greater physical fragility that occurs with age, with loss of protective muscle bulk and bone density.

Adulthood cognitive trajectories over 26 years and brain health at 70 years of age: findings from the 1946 British Birth Cohort.

Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n = 468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60-64 and 69 years) and was examined in relation to brain health markers of ß-amyloid (Aß) status, whole brain and hippocampal volume, and white matter hyperintensity volume (WMHV). Taking into account key contributors of adult cognitive decline including childhood cognition, those with greater Aß and WMHV at age 70 years had greater decline in word-list learning memory in the preceding 26 years, particularly after age 60. In contrast, those with smaller whole brain and hippocampal volume at age 70 years had greater decline in processing search speed, subtly manifest from age 50 years. Subtle changes in memory and processing speed spanning 26 years of adulthood were associated with markers of brain health at 70 years of age, consistent with detectable prodromal cognitive effects in early older age.

Delivery decision in pregnant women rescued by ECMO for severe ARDS: a retrospective multicenter cohort study.

BACKGROUND: Although rarely addressed in the literature, a key question in the care of critically pregnant women with severe acute respiratory distress syndrome (ARDS), especially at the time of extracorporeal membrane oxygenation (ECMO) decision, is whether delivery might substantially improve the mother's and child's conditions. This multicenter, retrospective cohort aims to report maternal and fetal short- and long-term outcomes of pregnant women with ECMO-rescued severe ARDS according to the timing of the delivery decision taken before or after ECMO cannulation. METHODS: We included critically ill women with ongoing pregnancy or within 15 days after a maternal/child-rescue-aimed delivery supported by ECMO for a severe ARDS between October 2009 and August 2021 in four ECMO centers. Clinical characteristics, critical care management, complications, and hospital discharge status for both mothers and children were collected. Long-term outcomes and premature birth complications were assessed. RESULTS: Among 563 women on venovenous ECMO during the study period, 11 were cannulated during an ongoing pregnancy at a median (range) of 25 (21-29) gestational weeks, and 13 after an emergency delivery performed at 32 (17-39) weeks of gestation. Pre-ECMO PaO2/FiO2 ratio was 57 (26-98) and did not differ between the two groups. Patients on ECMO after delivery reported more major bleeding (46 vs. 18%, p = 0.05) than those with ongoing pregnancy. Overall, the maternal hospital survival was 88%, which was not different between the two groups. Four (36%) of pregnant women had a spontaneous expulsion on ECMO, and fetal survival was higher when ECMO was set after delivery (92% vs. 55%, p = 0.03). Among newborns alive, no severe preterm morbidity or long-term sequelae were reported. CONCLUSION: Continuation of the pregnancy on ECMO support carries a significant risk of fetal death while improving prematurity-related morbidity in alive newborns with no difference in maternal outcomes. Decisions regarding timing, place, and mode of delivery should be taken and regularly (re)assess by a multidisciplinary team in experienced ECMO centers.