Identification of novel candidate autoantibodies in Alzheimer's disease.

BACKGROUND AND PURPOSE: Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, it is unknown whether autoantibodies are upregulated in amyloid-tau biomarker-confirmed AD. METHODS: A total of 40 subjects with mild dementia (Clinical Dementia Rating = 1) were stratified into AD (n = 16) and non-AD (n = 24) groups according to their cerebrospinal fluid levels of tau and Aß42 . Their sera were collected and analyzed using a microarray containing > 1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method with the following criteria: penetrance fold change(AD)  ≥ 2, frequency(AD)  ≥ 15% and frequency(non-AD)  = 0%. RESULTS: All controls and samples passed the quality control criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: nucleosome assembly protein 1-like 3 (31.3%, 5/16 subjects) and microtubule-associated protein 4, pantothenic acid kinase 3, phosphoinositide-3-kinase regulatory subunit 1, protein tyrosine phosphatase type IVA member 1 and SRY (sex-determining region Y)-box 15 (all 18.8%, 3/16 subjects). CONCLUSIONS: Although some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.

Progression of subcortical atrophy in mild Parkinson's disease and its impact on cognition.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD. METHODS: Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD-MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up. RESULTS: Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2-3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains. CONCLUSIONS: Progression of cognitive impairment in non-demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia.

Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region.

BACKGROUND: There is growing awareness of the coexistence of Alzheimer's disease and cerebrovascular disease (AD+CVD), however, due to lack of well-defined criteria and treatment guidelines AD+CVD may be underdiagnosed in Asia. METHODS: Sixteen dementia specialists from nine Asia Pacific countries completed a survey in September 2014 and met in November 2014 to review the epidemiology, diagnosis and treatment of AD+CVD in Asia. A consensus was reached by discussion, with evidence provided by published studies when available. RESULTS: AD accounts for up to 60% and AD+CVD accounts for 10-20% of all dementia cases in Asia. The reasons for underdiagnosis of AD+CVD include lack of awareness as a result of a lack of diagnostic criteria, misdiagnosis as vascular dementia or AD, lack of diagnostic facilities, resource constraints and cost of investigations. There is variability in the tools used to diagnose AD+CVD in clinical practice. Diagnosis of AD+CVD should be performed in a stepwise manner of clinical evaluation followed by neuroimaging. Dementia patients should be assessed for cognition, behavioural and psychological symptoms, functional staging and instrumental activities of daily living. Neuroimaging should be performed using computed tomography or magnetic resonance imaging. The treatment goals are to stabilize or slow progression as well as to reduce behavioural and psychological symptoms, improve quality of life and reduce disease burden. First-line therapy is usually an acetylcholinesterase inhibitor such as donepezil. CONCLUSION: AD+CVD is likely to be under-recognised in Asia. Further research is needed to establish the true prevalence of this treatable and potentially preventable disease.

Association between white matter hyperintensity and medial temporal atrophy at various stages of Alzheimer's disease.

BACKGROUND AND PURPOSE: Whilst there is evidence implicating small vessel cerebrovascular disease in the pathogenesis of Alzheimer's disease (AD), its specific contribution to the pathophysiology of AD remains unclear. The burden of small vessel cerebrovascular disease visualized as white matter hyperintensity (WMH) and its association with medial temporal atrophy (MTA) at different stages of AD was studied. METHODS: One hundred and sixty-five cognitively normal (CN) community controls, 103 mild cognitive impairment (MCI) patients, 141 mild AD patients and 68 moderate-severe AD patients were studied. Clinical, cognitive and risk factor data were collected, and WMH and MTA were quantified by trained raters. The Jonckheere-Terpstra test for ordered alternatives was used to study the association between WMH and MTA in different stages of AD. RESULTS: The burden of total WMH increased significantly with increasing severity of AD, even after correcting for confounders. The proportion of CN, MCI, mild AD and moderate-severe AD subjects with severe burden of WMH was 6.7%, 9.7%, 28.4%, and 39.7%, respectively. A strong positive association between WMH severity and MTA was evident amongst MCI (P = 0.011) and mild AD (P = 0.003) subjects, but not in CN (P = 0.953) and moderate-severe AD subjects (P = 0.301). CONCLUSIONS: The burden of WMH increased significantly from the stage of CN to MCI to AD. The association between WMH and MTA was greatest at the stage of MCI and mild AD. This has implications on the strategy to slow the progression of AD, where measures to reduce WMH, including control of vascular risk factors, need to be optimized at the stage of MCI and mild AD.

Validating a script concordance test for assessing neurological localization and emergencies.

BACKGROUND AND PURPOSE: Clinical judgment is the ability to weigh clinical information and make decisions under conditions of uncertainty. Although neurological localization (NL) and neurological emergencies (NE) present such uncertainties, no validated method is reported to assess these decision-making skills. A script concordance test (SCT) was designed and validated to assess clinical judgment in NL and NE. METHODS: Our SCT comprised 14 clinical scenarios (53 questions). Candidates picked the response they considered the best for the questions in each scenario. Undergraduates and internal medicine residents completed the SCT; their responses were scored against the scoring key derived from an expert panel of accredited neurologists. Scores were expressed as a percentage of the maximum score. RESULTS: Mean total scores for undergraduates (n = 52), residents (n = 37) and experts (n = 15) were 61.0 ± 0.9, 68.3 ± 1.1 and 76.6 ± 1.1 (mean ± standard error of the mean, P < 0.001). Mean scores for undergraduates, residents and experts were 59.3 ± 1.1, 66.4 ± 1.4 and 76.1 ± 1.8 (P < 0.001) for NL, and 62.9 ± 1.3, 70.4 ± 1.3 and 77.2 ± 1.6 (P < 0.001) for NE. Senior residents scored higher than junior residents (postgraduate years 2-5 versus postgraduate year 1, 69.7 ± 1.4 vs. 65.3 ± 1.1, P = 0.035). The higher scores with increasing clinical experience supports the construct validity of the SCT. The SCT showed acceptable reliability (G coefficient 0.74 ± 0.05). CONCLUSIONS: Our SCT is validated to reliably assess NL and NE in undergraduate and postgraduate learners; it is generalizable and feasible. It has potential as a valuable adjunct assessment tool for clinical judgment. Future plans to design SCTs to evaluate other topics in clinical neurology, as a multi-center study, are under way.

Association of Multi-Domain Factors with Cognition in the UK Biobank Study.

BACKGROUND: Dementia is a multifactorial syndrome attributable to a combination of vascular risk factors, lifestyle factors and neurodegeneration. However, little is known about the relative contribution of all these factors and their combined effects on cognition among the older population. OBJECTIVE: To examine the association of four domains of risk factors (sociodemographic, vascular risk factors, neuroimaging markers, lifestyle and psychosocial factors) with cognition in older adults. DESIGN: A cross-sectional study. SETTING: Data was obtained from a large-scale population-based study, UK Biobank study, at the first imaging visit assessment. PARTICIPANTS: Participants are citizen or permanent residents of UK, aged 60 years old and above. MEASURES: Cognitive function was assessed using the general cognitive ability score (g-factor score) derived from principal components analysis estimates of six cognitive tests. Associations with cognition were examined using multivariable linear regression for each domain and in combination. RESULTS: The study included 19,773 participants (mean age 68.5 ± 5.3 years SD, 9,726 (49%) male). Participants with lower cognitive scores (poorer cognition) were older, female, non-whites individuals, less educated and more socially deprived than participants with better cognitive scores. Participants with lower cognitive scores also tended to have higher vascular risk factors, lower brain volumes and more adverse lifestyle behaviours. The multivariable analysis found associations between adverse lifestyle and psychosocial factors with poorer cognition, i.e., being obese by measure of body fat percentage, having diabetes, higher white matter hyperintensity volume, increased sedentary screen time watching TV, being socially isolated and having depression were independently associated with poorer cognition. While larger hippocampal volume, having optimal sleep duration, adherence to a heathy diet, current and former alcohol drinking, increased wine consumption and sedentary screen time using a computer were associated with better cognition. CONCLUSION: A combination of adverse lifestyle and psychosocial factors were independently associated with poorer cognition in older adults. Findings in this study can potentially support public health communications to promote cognitive function and independence among older adults. This research has been conducted using the UK Biobank Resource under Application Number 71022.

Biomarkers and Cognition Study, Singapore (BIOCIS): Protocol, Study Design, and Preliminary Findings.

BACKGROUND: The focus of medicine is shifting from treatment to preventive care. The expression of biomarkers of dementia and Alzheimer's disease (AD) appear decades before the onset of observable symptoms, and evidence has emerged supporting pharmacological and non-pharmacological interventions to treat modifiable risk factors of dementia. However, there is limited research on the epidemiology, clinical phenotypes, and underlying pathobiology of cognitive diseases in Asian populations. OBJECTIVES: The objectives of the Biomarkers and Cognition Study, Singapore(BIOCIS) are to characterize the underlying pathobiology of Cognitive Impairment through a longitudinal study incorporating fluid biomarker profiles, neuroimaging, neuropsychological and clinical outcomes in a multi-ethnic Southeast Asian population. DESIGN, SETTING, PARTICIPANTS: BIOCIS is a 5-year longitudinal study where participants are assessed annually. 2500 participants aged 30 to 95 will be recruited from the community in Singapore. To investigate how pathology presents with or without minimal clinical symptoms and vice versa, CI and unimpaired individuals will be recruited. Participants will undergo assessments to characterise biomarkers of dementia through neuroimaging, fluid biomarkers, cognitive assessments, behavioural and lifestyle profiles, retinal scans and microbiome indicators. RESULTS: Since commencement of recruitment in February 2022, 1148 participants have been enrolled, comprising 1012 Chinese, 62 Indian, and 35 Malay individuals. Mean age and education is 61.32 years and 14.34 years respectively with 39.8% males. 47.9 % of the cohort are employed and 32.06% have a family history of dementia. The prevalence of cerebral small vessel disease is 90.2% with a mean modified Fazekas white matter hyperintensity score of 4.1. CONCLUSION: The BIOCIS cohort will help identify novel biomarkers, pathological trajectories, epidemiology of dementia, and reversible risk factors in a Southeast Asian population. Completion of BIOCIS longitudinal data could provide insights into risk-stratification of Asians populations, and potentially inform public healthcare and precision medicine for better patient outcomes in the prevention of Alzheimer's disease and dementia.

Post-stroke subjective cognitive impairment is associated with acute lacunar infarcts in the basal ganglia.

BACKGROUND AND PURPOSE: While recent studies have examined neuroimaging correlates of post-stroke mild cognitive impairment (MCI), no studies have examined neuroimaging correlates of post-stroke subjective cognitive impairment (SCI). METHODS: Consecutive patients with magnetic resonance imaging-confirmed acute lacunar strokes at a tertiary institute were recruited for this cross-sectional study. All patients underwent cognitive testing, and those with MCI were excluded from these analyses. Two independent neuroradiologists ascertained data on the number and location of any infarcts, as well as the degree of white matter hyperintensities. Multivariate logistic regression analyses were performed to study the association between neuroimaging markers and SCI. Only variables that were significant in the univariate stage and clinically relevant potential confounders were included in multivariable analyses. RESULTS: Of 145 patients evaluated, 48 patients with MCI were excluded from the study. Of the remaining 97 patients, 30 patients had SCI. In multivariable analyses, only mini-mental state examination (OR 0.61; CI 0.38-0.98) and basal ganglia infarcts (OR 8.19; CI 1.18-56.6) were significant predictors of SCI. CONCLUSION: In patients with acute lacunar strokes, we find that basal ganglia infarcts are associated with SCI. As the basal ganglia have been previously shown to be involved with learning of tasks, we hypothesize that infarcts in basal ganglia may affect learning speeds thereby contributing to the development of SCI. Larger studies are needed to confirm these results.

White Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework.

The AT(N) framework enables the classification of an individual within the biological Alzheimer's disease (AD) continuum by pairing the cognitive stage with the biomarker status of amyloid-beta (Aß, A), tau (T) and neurodegeneration (N). AD is a multifactorial disease that may involve different pathogenic mechanisms such as cerebrovascular disease (CVD). Therefore, biomarkers of these mechanisms can be added to the AT(N) framework to enhance the biomarker characterization of individuals within the AD continuum. In AD, white matter hyperintensities (WMH) which are postulated to develop as a result of chronic ischemia from small vessel CVD are shown to play a role in the aetiology. However, the interplay of WMH with Aß and tau pathophysiology in AD remains unclear. In this review, we summarized the studies that evaluated the associations between WMH and AD pathophysiology (Aß and tau). We found that the evidence supporting the association of WMH with Aß was mixed, and this may be explained by the relative contributions of WMH due to its differential load and anatomical distribution. More studies are also needed to determine the association of WMH with tau pathology. Future longitudinal studies with harmonized methodologies to quantify WMH and account for the anatomical differences of WMH are required to validate the relationship between WMH and AT(N) biomarkers. This will allow a clearer understanding of the utility of WMH as a vascular biomarker in the AT(N) framework. Novel CVD biomarkers will also have the potential to further elucidate the contributions of CVD to the AD pathophysiology.

The SINgapore GERiatric Intervention Study to Reduce Cognitive Decline and Physical Frailty (SINGER): Study Design and Protocol.

BACKGROUND: The SINgapore GERiatric intervention study to reduce cognitive decline and physical frailty (SINGER) randomised controlled trial (RCT) uses a multidomain lifestyle interventions approach, shown to be effective by the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial, to delay cognitive decline. OBJECTIVE: To investigate the efficacy and safety of the SINGER multidomain lifestyle interventions in older adults at risk for dementia to delay cognitive decline. PARTICIPANTS: 1200 participants between 60-77 years old, with Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score ≥6, fulfilling at least one of the following LIBRA index for diet, cognitive activity, physical activity and a Montreal Cognitive Assessment (MoCA) score ≥18, ≤27 points, will be recruited across Singapore. METHODS: SINGER is a 2-year multi-site RCT consisting of multidomain interventions: dietary advice, exercise, cognitive training, and vascular risk factors management. Participants will be randomised into either the Self-Guided Intervention (SGI; general lifestyle and health information and resources) or Structured Lifestyle Intervention (SLI) group. The SLI comprises diet training (6 group and 3 individual sessions over 12 months); exercise (supervised: 1-hour twice weekly for 6 months, unsupervised: 2-3/week for the rest of the study duration); cognitive sessions (15-30 minutes/session, 3/week for 6 months, together with 10 workshops in 24 months). Vascular management takes place every 3-6 months or otherwise as specified by study physicians. The primary outcome is global cognition measured using the modified Neuropsychological Battery assessing performance in various domains, such as episodic memory, executive function and processing speed. Secondary outcome measures include: domain-specific cognition and function, imaging evidence of brain and retinal changes, incidence and progression of chronic diseases, blood biomarkers, quality of life, mental health and cost-benefit analysis. CONCLUSIONS: SINGER is part of the Worldwide-FINGERS international network, which is at the forefront of harmonizing approaches to effective non-pharmacological interventions in delaying cognitive decline in older adults at risk of dementia. By establishing the efficacy of multidomain interventions in preventing cognitive decline, SINGER aims to implement the findings into public health and clinical practices by informing policy makers, and guiding the design of community- and individual-level health promotion initiatives.

Cognitive screening in Asia: recognizing the role of the patient-family unit.

BACKGROUND/AIMS: Cognitive screening programmes may improve awareness and help at-risk subjects receive earlier medical attention. Cognitive profiles of subjects who attend cognitive screening by personal choice (self-referred) compared to those where the referral was initiated by family members (family-referred) were compared. METHODS: A cross-sectional survey of community subjects attending a cognitive screening initiative. Performance on the MMSE, Frontal Assessment Battery (FAB), Elderly Cognitive Assessment Questionnaire (ECAQ) and Even Briefer Assessment Scale for Depression was evaluated. RESULTS: A total of 342 subjects with a mean age of 59.2 +/- 9.0 years were screened. Overrepresentation of Chinese and Indian subjects and underrepresentation of Malay subjects was noted. The prevalence of cognitive impairment ranged from 7.0 to 9.6% depending on the screening instrument used. Of the 342 subjects, 267 were self-referred, while 75 subjects were family-referred. Family-referred subjects had lower MMSE (p < 0.001), lower ECAQ (p < 0.001) and lower FAB (p < 0.001) scores but were not more depressed compared to self-referred subjects (p = 0.904). Only the difference in ECAQ scores remained significant after adjustment for baseline differences in age and education. The prevalence of hypertension, diabetes mellitus and hypercholesterolaemia was not statistically different between the 2 groups. CONCLUSIONS: Family members play a crucial role in the diagnosis of cognitive impairment, especially in older subjects with fewer years of education.

Differences exist in the cognitive profile of mild Alzheimer's disease and subcortical ischemic vascular dementia.

BACKGROUND/AIMS: Our objective was to characterize the cognitive profile of patients with mild Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD) matched using a functional scale. METHODS: AD and SIVD were diagnosed using the NINCDS-ADRDA and the criteria proposed by Erkinjuntti et al., respectively. The Clinical Dementia Rating (CDR) scale was used to guide the identification of patients with mild dementia from a prospective clinical database. Regression analysis was applied to compare the 2 groups on global and individual cognitive domains. RESULTS: The greatest cognitive differences between the 2 groups were observed in the domains of visuospatial function (p = 0.001), working memory (p = 0.013) and visuomotor speed (p = 0.028). No significant variation was demonstrated in the executive function domain (p = 0.646). Statistically significant differences between AD and SIVD patients were found in episodic memory delayed recall tasks but not in the immediate recall tasks. A trend towards severer depressive symptoms (p = 0.052) was observed among the SIVD patients. CONCLUSIONS: SIVD patients with mild dementia have greater deficits in visuospatial function, working memory and visuomotor speed and may also be more depressed compared to AD patients. Executive function tests in general do not distinguish the 2 groups, although timed executive tasks can separate them.

Creutzfeldt-Jakob disease: which diffusion-weighted imaging abnormality is associated with periodic EEG complexes?

BACKGROUND: Clinical diagnosis of CJD remains important due to lack of access to a genetic or histopathological diagnosis. Using current WHO criteria, diagnostic certainty can be increased from "possible" to "probable" CJD if periodic complexes are recorded on EEG. OBJECTIVE: To study the correlation between patterns of MRI-DWI hyperintensity and typical EEG findings among patients with CJD. METHODS: Demographics, clinical findings, MRI-DWI and EEG findings of CJD patients were retrospectively reviewed. RESULTS: A total of 14 patients ranging in age from 35 to 81 years were identified. All had dementia and cerebellar ataxia. Psychiatric manifestations were seen in 5 patients. Seven patients had both cortical and striatal DWI changes, five had isolated cortical DWI changes and two had isolated striatal DWI changes. All twelve patients with cortical DWI changes also had periodic EEG changes. In ten, periodic EEG was recorded within seven days of the DWI. The two patients with isolated striatal DWI changes did not develop periodic EEG complexes despite serial EEG recordings, 40 and 88 days from their respective DWI scans. CONCLUSIONS: Serial EEGs are not useful for patients with isolated striatal DWI hyperintensity but will increase diagnostic certainty from "possible" to probable" CJD for patients with cortical DWI hyperintensity.

Subcortical atrophy is associated with cognitive impairment in mild Parkinson disease: a combined investigation of volumetric changes, cortical thickness, and vertex-based shape analysis.

BACKGROUND AND PURPOSE: The involvement of subcortical deep gray matter and cortical thinning associated with mild Parkinson disease remains poorly understood. We assessed cortical thickness and subcortical volumes in patients with Parkinson disease without dementia and evaluated their associations with cognitive dysfunction. MATERIALS AND METHODS: The study included 90 patients with mild Parkinson disease without dementia. Neuropsychological assessments classified the sample into patients with mild cognitive impairment (n = 25) and patients without cognitive impairment (n = 65). Volumetric data for subcortical structures were obtained by using the FMRIB Integrated Registration and Segmentation Tool while whole-brain, gray and white matter volumes were estimated by using Structural Image Evaluation, with Normalization of Atrophy. Vertex-based shape analyses were performed to investigate shape differences in subcortical structures. Vertex-wise group differences in cortical thickness were also assessed. Volumetric comparisons between Parkinson disease with mild cognitive impairment and Parkinson disease with no cognitive impairment were performed by using ANCOVA. Associations of subcortical structures with both cognitive function and disease severity were assessed by using linear regression models. RESULTS: Compared with Parkinson disease with no cognitive impairment, Parkinson disease with mild cognitive impairment demonstrated reduced volumes of the thalamus (P = .03) and the nucleus accumbens (P = .04). Significant associations were found for the nucleus accumbens and putamen with performances on the attention/working memory domains (P < .05) and nucleus accumbens and language domains (P = .04). The 2 groups did not differ in measures of subcortical shape or in cortical thickness. CONCLUSIONS: Patients with Parkinson disease with mild cognitive impairment demonstrated reduced subcortical volumes, which were associated with cognitive deficits. The thalamus, nucleus accumbens, and putamen may serve as potential biomarkers for Parkinson disease-mild cognitive impairment.

A strategy for reducing maternal mortality.

A confidential system of enquiry into maternal mortality was introduced in Malaysia in 1991. The methods used and the findings obtained up to 1994 are reported below and an outline is given of the resulting recommendations and actions.

PIP: This is a report on the methods, findings, resulting recommendations and actions of a study on maternal mortality in Malaysia during the period 1991-94. Maternal death was defined as the death of a woman while pregnant or within 42 days following termination of pregnancy from any cause related to the pregnancy or its management but not from accidental causes. Between 1991 and 1994 there were 1066 reported maternal deaths, and the maternal mortality ratios for the successive years were respectively 44, 48, 46 and 39 per 100,000 live births. The primary causes of maternal death were postpartum hemorrhage (24%), hypertensive disorders of pregnancy (16%), obstetric pulmonary embolism (13%), and associated medical conditions (7%). Analysis of the 375 deaths from 1992 - 1993 showed that the maternal mortality ratio was 53/100,000 live births for deliveries performed at home, 36/100,000 in government hospitals, and 21/100,000 in private institutions. Shortcomings among health personnel were detected in several cases; these involved failure to diagnose, failure to appreciate the severity of a patient's condition, inadequate therapy, and inappropriate, delayed or failed adherence to protocols. The high proportion of maternal mortality associated with substandard care demonstrates that it is important to make the standard of care more widely available. Reports have been circulated to institutions and organizations providing maternal care and to medical schools. Articles and case histories have been published, and many new protocols and procedures have been developed. Furthermore, seminars have been organized and training modules have been distributed to all involved in the provision of maternity care.