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.

Management of Malignant Bowel Obstruction: An Innovative Proactive Outpatient Nurse-Led Model of Care for Patients With Advanced Gynecologic Cancer.

BACKGROUND: Malignant bowel obstruction (MBO) in patients with advanced gynecologic cancer (GyCa) can negatively impact clinical outcomes and quality of life. Oncology nurses can support these patients with adequate tools/processes. PROBLEM: Patients with GyCa with/at risk of MBO endure frequent emergency or hospital admissions, impacting patient care. APPROACH: Optimizing oncology nurses' role to improve care for patients with GyCa with/at risk of MBO, the gynecology oncology interprofessional team collaborated to develop a proactive outpatient nurse-led MBO model of care (MOC). OUTCOMES: The MBO MOC involves a risk-based algorithm engaging interdisciplinary care, utilizing standardized tools, risk-based assessment, management, and education for patients and nurses. The MOC has improved patient-reported confidence level of bowel self-management and decreased hospitalization. Following education, nurses demonstrated increased knowledge in MBO management. CONCLUSIONS: An outpatient nurse-led MBO MOC can improve patient care and may be extended to other cancer centers, fostering collaboration and best practice.

Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.

Alzheimer's disease has a preclinical stage when cerebral amyloid-ß deposition occurs before symptoms emerge, and when amyloid-ß-targeted therapies may have maximum benefits. Existing amyloid-ß status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-ß, and single molecule array (Simoa) measures of plasma amyloid-ß and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628-0.762). The two best-performing Simoa plasma biomarkers were amyloid-ß42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-ß1-42/1-40: 0.817; 0.770-0.864 and amyloid-ß composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-ß1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-ß1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-ß1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.

Subjective cognitive complaints at age 70: associations with amyloid and mental health.

OBJECTIVE: To investigate subjective cognitive decline (SCD) in relation to ß-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study. METHODS: Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to 18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant's perspective on SCD was evaluated in relation to MyCog score. RESULTS: Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) -0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant's perception of SCD was generally in accordance with that of the participant. CONCLUSIONS: This cross-sectional study demonstrates that symptoms of SCD are associated with both ß-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer's disease pathology and SCD.

Mild Parkinsonian Signs: A Systematic Review of Clinical, Imaging, and Pathological Associations.

Mild parkinsonian signs (MPS) have been widely studied during the past 3 decades and proposed as a risk marker for neurodegenerative disease. This systematic review explores the epidemiology, clinical and prognostic associations, radiological features, and pathological findings associated with MPS in older adults free from neurodegenerative disease. We find that MPS as currently defined are strongly associated with increasing age and increased risk of development of Parkinson's disease (PD), all-cause dementia, disability, and death. Positive associations with later PD are found mainly in younger populations and those with other features of prodromal PD. There are currently no consistent radiological findings for MPS, and pathological studies have shown that MPS, at least in the oldest old, are often underpinned by mixed neuropathologies, including those associated with Alzheimer's disease, cerebrovascular disease, nigral neuronal loss, and Lewy bodies. Different subcategories of MPS appear to convey varying risk and specificity for PD and other outcomes. MPS overall are not specific for parkinsonian disorders and, although associated with increased risk of PD, can reflect multiple pathologies, particularly in older individuals. "Mild motor signs" appears a more appropriate term to avoid prognostic and pathological implications, and larger future studies to prospectively examine outcomes and associations of specific MPS subcategories are required. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diet quality in late midlife is associated with faster walking speed in later life in women, but not men: findings from a prospective British birth cohort.

Healthy diet has been linked to better age-related functioning, but evidence on the relationship of diet quality in late midlife and measures of physical capability in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 (HEI-2015) at 60-64 years and measures of walking speed 7 years later, among men and women from the Insight 46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at 60-64 years using 5-d food diaries, from which total HEI-2015 was calculated. At 69-71 years, walking speed was estimated during four 10-m walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as a modifier, controlling for age, follow-up, lifestyle, health/social variables and physical performance, were used. The final sample consists of 164 women and 167 men (n 331). Women had higher HEI-2015 and slower walking speed than men. A 10-point increase in HEI-2015 was associated with faster walking speed among women (B 0·024, 95 % CI 0·006, 0·043), but not men. The association remained significant in the multivariable model (B 0·021, 95 % CI 0·003, 0·040). In women, higher diet quality in late midlife is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability, and sex differences are likely to affect this relationship.

Allostatic load and ageing: linking the microbiome and nutrition with age-related health.

Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome.Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the 'diseasome' of ageing. Additionally, it can be influenced by the 'foodome', via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape.

Epigenetic alterations, such as those linked to DNA methylation, may potentially provide molecular explanations for complications associated with altered gene expression in illnesses, such as chronic kidney disease (CKD). Although both DNA hypo- and hypermethylation have been observed in the uremic milieu, this remains only a single aspect of the epigenetic landscape and, thus, of any biochemical dysregulation associated with CKD. Nevertheless, the role of uremia-promoting alterations on the epigenetic landscape regulating gene expression is still a novel and scarcely studied field. Although few studies have actually reported alterations of DNA methylation via methyl donor nutrient intake, emerging evidence indicates that nutritional modification of the microbiome can affect one-carbon metabolism and the capacity to methylate the genome in CKD. In this review, we discuss the nutritional modifications that may affect one-carbon metabolism and the possible impact of methyl donor nutrients on the microbiome, CKD, and its phenotype.

Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome.

BACKGROUND: Current management of preterm prelabour rupture of the membranes (PPROM) involves either initiating birth soon after PPROM or, alternatively, adopting a 'wait and see' approach (expectant management). It is unclear which strategy is most beneficial for mothers and their babies. This is an update of a Cochrane review published in 2010 (Buchanan 2010). OBJECTIVES: To assess the effect of planned early birth versus expectant management for women with preterm prelabour rupture of the membranes between 24 and 37 weeks' gestation for fetal, infant and maternal well being. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (30 September 2016), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing planned early birth with expectant management for women with PPROM prior to 37 weeks' gestation. We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated trials for inclusion into the review and for methodological quality. Two review authors independently extracted data. We checked data for accuracy. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 12 trials in the review (3617 women and 3628 babies). For primary outcomes, we identified no clear differences between early birth and expectant management in neonatal sepsis (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30, 12 trials, 3628 babies, evidence graded moderate), or proven neonatal infection with positive blood culture (RR 1.24, 95% CI 0.70 to 2.21, seven trials, 2925 babies). However, early birth increased the incidence of respiratory distress syndrome (RDS) (RR 1.26, 95% CI 1.05 to 1.53, 12 trials, 3622 babies, evidence graded high). Early birth was also associated with an increased rate of caesarean section (RR 1.26, 95% CI 1.11 to 1.44, 12 trials, 3620 women, evidence graded high).Assessment of secondary perinatal outcomes showed no clear differences in overall perinatal mortality (RR 1.76, 95% CI 0.89 to 3.50, 11 trials, 3319 babies), or intrauterine deaths (RR 0.45, 95% CI 0.13 to 1.57, 11 trials, 3321 babies) when comparing early birth with expectant management. However, early birth was associated with a higher rate of neonatal death (RR 2.55, 95% CI 1.17 to 5.56, 11 trials, 3316 babies) and need for ventilation (RR 1.27, 95% CI 1.02 to 1.58, seven trials, 2895 babies, evidence graded high). Babies of women randomised to early birth were delivered at a gestational age lower than those randomised to expectant management (mean difference (MD) -0.48 weeks, 95% CI -0.57 to -0.39, eight trials, 3139 babies). Admission to neonatal intensive care was more likely for those babies randomised to early birth (RR 1.16, 95% CI 1.08 to 1.24, four trials, 2691 babies, evidence graded moderate).In assessing secondary maternal outcomes, we found that early birth was associated with a decreased rate of chorioamnionitis (RR 0.50, 95% CI 0.26 to 0.95, eight trials, 1358 women, evidence graded moderate), and an increased rate of endometritis (RR 1.61, 95% CI 1.00 to 2.59, seven trials, 2980 women). As expected due to the intervention, women randomised to early birth had a higher chance of having an induction of labour (RR 2.18, 95% CI 2.01 to 2.36, four trials, 2691 women). Women randomised to early birth had a decreased total length of hospitalisation (MD -1.75 days, 95% CI -2.45 to -1.05, six trials, 2848 women, evidence graded moderate).Subgroup analyses indicated improved maternal and infant outcomes in expectant management in pregnancies greater than 34 weeks' gestation, specifically relating to RDS and maternal infections. The use of prophylactic antibiotics were shown to be effective in reducing maternal infections in women randomised to expectant management.Overall, we assessed all 12 studies as being at low or unclear risk of bias. Some studies lacked an adequate description of methods and the risk of bias could only be assessed as unclear. In five of the studies there were one and/or two domains where the risk of bias was judged as high. GRADE profiling showed the quality of evidence across all critical outcomes to be moderate to high. AUTHORS' CONCLUSIONS: With the addition of five randomised controlled trials (2927 women) to this updated review, we found no clinically important difference in the incidence of neonatal sepsis between women who birth immediately and those managed expectantly in PPROM prior to 37 weeks' gestation. Early planned birth was associated with an increase in the incidence of neonatal RDS, need for ventilation, neonatal mortality, endometritis, admission to neonatal intensive care, and the likelihood of birth by caesarean section, but a decreased incidence of chorioamnionitis. Women randomised to early birth also had an increased risk of labour induction, but a decreased length of hospital stay. Babies of women randomised to early birth were more likely to be born at a lower gestational age.In women with PPROM before 37 weeks' gestation with no contraindications to continuing the pregnancy, a policy of expectant management with careful monitoring was associated with better outcomes for the mother and baby.The direction of future research should be aimed at determining which groups of women with PPROM would not benefit from expectant management. This could be determined by analysing subgroups according to gestational age at presentation, corticosteroid usage, and abnormal vaginal microbiological colonisation. Research should also evaluate long-term neurodevelopmental outcomes of infants.

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.

Operationalizing the centiloid scale for [18F]florbetapir PET studies on PET/MRI.

INTRODUCTION: The Centiloid scale aims to harmonize amyloid beta (Aß) positron emission tomography (PET) measures across different analysis methods. As Centiloids were created using PET/computerized tomography (CT) data and are influenced by scanner differences, we investigated the Centiloid transformation with data from Insight 46 acquired with PET/magnetic resonanceimaging (MRI). METHODS: We transformed standardized uptake value ratios (SUVRs) from 432 florbetapir PET/MRI scans processed using whole cerebellum (WC) and white matter (WM) references, with and without partial volume correction. Gaussian-mixture-modelling-derived cutpoints for Aß PET positivity were converted. RESULTS: The Centiloid cutpoint was 14.2 for WC SUVRs. The relationship between WM and WC uptake differed between the calibration and testing datasets, producing implausibly low WM-based Centiloids. Linear adjustment produced a WM-based cutpoint of 18.1. DISCUSSION: Transformation of PET/MRI florbetapir data to Centiloids is valid. However, further understanding of the effects of acquisition or biological factors on the transformation using a WM reference is needed. HIGHLIGHTS: Centiloid conversion of amyloid beta positron emission tomography (PET) data aims to standardize results.Centiloid values can be influenced by differences in acquisition.We converted florbetapir PET/magnetic resonance imaging data from a large birth cohort.Whole cerebellum referenced values could be reliably transformed to Centiloids.White matter referenced values may be less generalizable between datasets.

Dementia Prevention Research Clinic: a longitudinal study investigating factors influencing the development of Alzheimer's disease in Aotearoa, New Zealand.

Aotearoa New Zealand's population is ageing. Increasing life expectancy is accompanied by increases in prevalence of Alzheimer's Disease (AD) and ageing-related disorders. The multicentre Dementia Prevention Research Clinic longitudinal study aims to improve understanding of AD and dementia in Aotearoa, in order to develop interventions that delay or prevent progression to dementia. Comprising research clinics in Auckland, Christchurch and Dunedin, this multi-disciplinary study involves community participants who undergo biennial investigations informed by international protocols and best practice: clinical, neuropsychological, neuroimaging, lifestyle evaluations, APOE genotyping, blood collection and processing. A key research objective is to identify a 'biomarker signature' that predicts progression from mild cognitive impairment to AD. Candidate biomarkers include: blood proteins and microRNAs, genetic, neuroimaging and neuropsychological markers, health, cultural, lifestyle, sensory and psychosocial factors. We are examining a range of mechanisms underlying the progression of AD pathology (e.g. faulty blood-brain barrier, excess parenchymal iron, vascular dysregulation). This paper will outline key aspects of the Dementia Prevention Research Clinic's research, provide an overview of data collection, and a summary of 266 participants recruited to date. The national outreach of the clinics is a strength; the heart of the Dementia Prevention Research Clinics are its people.

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.

Trends and morbidity associated with oxytocin use in labour in nulliparas at term.

AIM: To determine the trends in oxytocin use at a population level within New South Wales and to assess the maternal and neonatal morbidities associated with the use of oxytocin. METHODS: Trends in oxytocin use were assessed for women in NSW who were nulliparas at term with a singleton, cephalic fetus between 1998 and 2008. Maternal and neonatal morbidities were assessed in 2007-2008 using linked hospital and birth data with regression analysis. Oxytocin was also assessed by indication for use being either induction or augmentation of labour. RESULTS: The overall use of oxytocin increased from 10,291 (36.5%) of births in 1998 to 14,440 (45.4%) of births in 2008 (P < 0.0001) with the increase entirely because of the increased use for induction of labour. The use of oxytocin was associated with an increase in regional analgesia (65 to 22%), instrumental delivery (21 to 18%) and caesarean section (29 to 14%) as compared to women who did not receive oxytocin in labour. Oxytocin was also associated with an increase in severe maternal adjusted odds ratios ((aOR) 1.48, 95% CI 1.30-1.68) and neonatal morbidity (aOR 1.29, 95% CI 1.17-1.41). This increase in morbidity was maintained when both augmentation and induction were assessed separately. CONCLUSION: Oxytocin has an important role in the management of labour. However, its use should be carefully monitored with standardised treatment regimes to minimise maternal and neonatal morbidity.

The psychosocial needs of patients who have chronic kidney disease without kidney replacement therapy: a thematic synthesis of seven qualitative studies.

BACKGROUND: Limited quantitative data suggests that patients who have chronic kidney disease without kidney replacement therapy (CKD without KRT) may present with psychosocial needs just as patients who have acute kidney injury and are treated by dialysis (AKI stage 3D) do. This systematic review aims to synthesise qualitative research on patients' experiences of CKD without KRT to provide further insight into patients' experience of the healthcare they receive and simultaneously, their psychosocial needs, to inform the development of appropriate psychological interventions. METHODS: The review followed ENTREQ guidelines. PubMed/MEDLINE, PsycINFO, EMBASE and CINAHL were searched in July and August 2021. Qualitative studies in English on the experiences of CKD without KRT care were included in the review. Thematic synthesis was conducted on the findings of the included studies. RESULTS: The search identified 231 articles for screening. Eight studies met the inclusion criteria, and one was excluded at the quality assessment stage. The final seven articles [n = 130 patients] were analysed. Five themes on psychosocial needs were developed: addressing patients' CKD-related educational needs, supporting the patient's relationships, honouring the patient's need for control, adjusting to change, and recognising fear of disease and treatment. DISCUSSION: This review highlights the range of psychosocial needs of patients who have CKD without KRT. There are numerous intervention options that clinicians may develop that could benefit patients and address multiple needs, such as group educational programmes.

Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study.

BACKGROUND: A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age. METHODS: Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy. FINDINGS: Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (ß=2·3 [95% CI 1·5 to 3·0]) and 69 years (ß=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD. INTERPRETATION: Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility. FUNDING: Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

Associations of ß-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort.

BACKGROUND AND OBJECTIVES: The goals of this work were to quantify the independent and interactive associations of ß-amyloid (Aß) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort. METHODS: Participants underwent brain MRI and florbetapir-Aß PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral. Linear regression was used to test associations with baseline Aß deposition, baseline WMHV, APOE ε4, and office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53, and 69 years. RESULTS: Three hundred forty-six cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time points (mean [SD] scan interval 2.4 [0.2] years). Being Aß positive at baseline was associated with 0.87-mL/y faster whole-brain atrophy (95% CI 0.03, 1.72), 0.39-mL/y greater ventricular expansion (95% CI 0.16, 0.64), and 0.016-mL/y faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10-mL additional WMHV at baseline was associated with 1.07-mL/y faster whole-brain atrophy (95% CI 0.47, 1.67), 0.31-mL/y greater ventricular expansion (95% CI 0.13, 0.60), and 0.014-mL/y faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent, and there was no evidence that Aß and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjustment for Aß status and WMHV, no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, and no evidence that FHS-CVS or systolic BP acted synergistically with Aß. DISCUSSION: Aß and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways.

Socioeconomic position links circulatory microbiota differences with biological age.

Imbalanced nutrition is associated with accelerated ageing, possibly mediated by microbiota. An analysis of the circulatory microbiota obtained from the leukocytes of participants in the MRC Twenty-07 general population cohort was performed. We now report that in this cohort, the most biologically aged exhibit a significantly higher abundance of circulatory pathogenic bacteria, including Neisseria, Rothia and Porphyromonas, while those less biologically aged possess more circulatory salutogenic (defined as being supportive of human health and wellbeing) bacteria, including Lactobacillus, Lachnospiraceae UCG-004 and Kocuria. The presence of these salutogenic bactreria is consistent with a capacity to metabolise and produce Nrf2 agonists. We also demonstrate that associated one carbon metabolism, notably betaine levels, did not vary with chronological age, but displayed a difference with socioeconomic position (SEP). Those at lower SEP possessed significantly lower betaine levels indicative of a poorer diet and poorer health span and consistent with reduced global DNA methylation levels in this group. Our data suggest a clear route to improving age related health and resilience based on dietary modulation of the microbiota.

Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays.

INTRODUCTION: We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aß) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET). METHODS: In 72 individuals from the Insight 46 study, CSF Aß40, Aß42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays and inter-platform Pearson correlations derived. Lumipulse Aß42 measures were adjusted to incorporate standardization to certified reference materials. Logistic regressions and receiver operating characteristics analysis generated CSF cut-points optimizing concordance with 18F-florbetapir amyloid PET status (n = 63). RESULTS: Measurements of CSF Aß, p-tau181, and their ratios correlated well across platforms (r 0.84 to 0.94, P < .0001); those of t-tau and t-tau/Aß42 correlated moderately (r 0.57 to 0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.075 for Lumipulse Aß42/Aß40, 0.087 for MSD Aß42/Aß40 and 17.3 for Lumipulse Aß42/p-tau181. DISCUSSION: The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology.