Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

Disability accrual in primary and secondary progressive multiple sclerosis.

BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

Comparative effectiveness in multiple sclerosis: A methodological comparison.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Superior effects of natalizumab versus other DMTs on patient-reported outcomes in people with multiple sclerosis.

BACKGROUND: Little is known about the comparative effectiveness of multiple sclerosis (MS) disease-modifying therapies (DMTs) on patient-reported outcomes in MS. We compared the effects of natalizumab to other DMTs in relation to MS symptom severity, quality of life, disability, disease progression and employment outcomes using real-world data. METHODS: We included 2817 observations in 2015, 2016 and 2017 from 1382 participants in the Australian MS Longitudinal Study. Information on treatment, health and employment outcomes was prospectively collected by questionnaires. Marginal structural models with interaction terms for DMT×time were used to compare natalizumab and other comparator treatment groups. RESULTS: Natalizumab was associated with improvements over time, or general trends of improvement, in the severity of many symptoms and work productivity loss. Compared with any other DMTs, natalizumab was associated with superior effects over time for 8 of 23 patient-reported outcomes, with similar directions of effect observed for another 6, demonstrating consistency. There were no differences in effect for spasticity, fatigue, pain, feelings of depression, disability, European quality of life five dimension index, presenteeism and work status. Natalizumab did not perform significantly worse over time compared with any other DMTs for any of the outcomes. CONCLUSIONS: Natalizumab was associated with superior outcomes over time for many patient-reported health and employment outcomes when compared with other DMTs in this large prospective cohort study. These findings may influence treatment selection in clinical practice and future treatment cost-effectiveness analyses.

Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry.

BACKGROUND: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. OBJECTIVE: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. METHODS: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. RESULTS: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(ß)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). CONCLUSIONS: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.

A comparison of macular ganglion cell and retinal nerve fibre layer optical coherence tomographic parameters as predictors of visual outcomes of surgery for pituitary tumours.

PURPOSE: The prognostic value of optical coherence tomography (OCT) of the macular ganglion cell layer (mGGL) versus peripapillary retinal nerve fibre layers (pRNFL) following chiasmal decompression is unclear. This study is the largest comparison of the two parameters to date and aims to clarify how their performance as covariates compare in predictive models of long-term visual outcomes following pituitary or parasellar tumour surgical resection. METHODS: This was a prospective, two-year, longitudinal cohort study in a single centre tertiary hospital setting. Participants with MRI evidence of pituitary or parasellar tumour compression of the optic chiasm who underwent surgical decompression, were enrolled. Associations between pre-operative OCT parameters and long-term visual outcomes were assessed using multivariable generalised linear mixed models and an age matched normative database. RESULTS: Final analysis included 216 eyes of 108 participants with a mean age (standard deviation) of 51.6 (17.04) years, of whom 58 (49%) were female. The superior inner mGCL was the best predictor of long-term visual field recovery, with an area under the curve of 0.90, a sensitivity of 80%, specificity of 88%, positive predictive value of 86%, and negative predictive value of 83%. CONCLUSION: mGCL performed better in predicting long-term visual field recovery post-pituitary or parasellar surgical resection. The superior inner mGCL was the best specific measure which may provide clinical utility in pre-operative counselling. In this study we clarify previously variable comparisons of mGCL and pRNFL parameters in post-operative predictive modelling.

Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives.

OBJECTIVE: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. METHODS: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59). RESULTS: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]). CONCLUSION: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.

Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology.

Cortical iron has been shown to be elevated in Alzheimer's disease (AD), but the impact of the directly measured iron on the clinical syndrome has not been assessed. We investigated the association between post-mortem iron levels with the clinical and pathological diagnosis of AD, its severity, and the rate of cognitive decline in the 12 years prior to death in subjects from the Memory and Aging Project (n = 209). Iron was elevated (ß [SE] = 9.7 [2.6]; P = 3.0 × 10-4) in the inferior temporal cortex only in subjects who were diagnosed with clinical AD during life and had a diagnosis of AD confirmed post-mortem by standardized criteria. Although iron was weakly associated with the extent of proteinopathy in tissue with AD neuropathology, it was strongly associated with the rate of cognitive decline (e.g., global cognition: ß [SE] = -0.040 [0.005], P = 1.6 × 10-14). Thus, cortical iron might act to propel cognitive deterioration upon the underlying proteinopathy of AD, possibly by inducing oxidative stress or ferroptotic cell death, or may be related to an inflammatory response.

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance.

OBJECTIVE: This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large-scale emerging evidence. BACKGROUND: Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. NEW/UPDATED HYPOTHESIS: We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. MAJOR CHALLENGES FOR THE HYPOTHESIS: While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti-ferroptotic/iron compound in AD patients. LINKAGE TO OTHER MAJOR THEORIES: Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well-established consequence of aging and inflammation, which are major theories of disease pathogenesis.

Cerebrospinal fluid ceruloplasmin levels predict cognitive decline and brain atrophy in people with underlying ß-amyloid pathology.

OBJECTIVES: The mechanisms leading to neurodegeneration in Alzheimer's disease (AD) may involve oxidative stress and neuroinflammation. Ceruloplasmin (Cp) is a circulating protein that intersects both these pathways, since its expression is increased during the acute phase response, and the protein acts to lower pro-oxidant iron in cells. Since the role of Cp in AD, and its potential for use as a biomarker is not established, we investigated CSF Cp and its association with longitudinal outcome measures related to AD. METHODS: This was an observational study of 268 people from the Alzheimer's Disease Neuroimaging (ADNI) cohort. Subjects were classified clinically as having AD, mild cognitive impairment (MCI) or were cognitively normal (CN), and were also classified as being positive for ß-amyloid using established thresholds in the CSF t-tau/Aß42 ratio. Subjects underwent cognitive tests and MRI studies every 6 months for 2 years, then yearly thereafter for up to 6 years. RESULTS: At baseline, CSF Cp was not associated with clinical or pathological diagnosis, but we found an unexpected association between CSF Cp and levels of CSF apolipoprotein E. In longitudinal analysis, high level of CSF Cp was associated with accelerated cognitive decline (as assessed by ADAS-Cog, CDR-SB, and MMSE) and ventricular volume enlargement in people classified as MCI and who had underlying ß-amyloid pathology. CONCLUSION: These results raise new questions into the role of Cp in neuroinflammation, oxidative stress, and APOE pathways involved in AD, and reveal the potential for this protein to be used as a biomarker in disease prognostication.

Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying ß-amyloid pathology.

ß-Amyloid pathology is elevated in ~30% of cognitively normal people over 65, and is associated with accelerated neurodegeneration in the pre-clinical stages of Alzheimer's disease. Recent findings reveal that brain iron might also act to propel neurodegeneration in people with underlying amyloid pathology. Here, repeated PET scans of fluorodeoxyglucose (FDG) were used as a biomarker for brain hypometabolism and a downstream biomarker of neurodegeneration to investigate whether levels of ferritin in the cerebrospinal fluid (CSF; a reporter of brain iron load) are associated with prodromal disease progression of people with high ß-amyloid pathology determined by established cut-off values in CSF t-tau/Aß42 ratio. Nineteen cognitively normal participants with low t-tau/Aß42, and 71 participants with high t-tau/Aß42 who were cognitively normal or had mild cognitive impairment were included as participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. These subjects had repeated FDG-PET scans at 6-month intervals for 2 years, and yearly intervals for up to a further 3 years. In mixed-effects linear models of FDG signal, baseline CSF ferritin was associated with an accelerated decline in FDG PET in high t-tau/Aß42 participants (ß[SE] = -0.066 [0.017]; P = .0002), but not in people with low t-tau/Aß42 (-0.029 [0.049]; P = .554). These data implicate iron as a contributing factor to neurodegeneration associated with ß-amyloid pathology, and highlight CSF ferritin as a complementary prognostic biomarker to the t-tau/Aß42 ratio that predicts near-term risk for disease progression.

For more than money: willingness of health professionals to stay in remote Senegal.

BACKGROUND: Poor distribution of already inadequate numbers of health professionals seriously constrains equitable access to health services in low- and middle-income countries. The Senegalese Government is currently developing policy to encourage health professionals to remain in areas defined as 'difficult'. Understanding health professional's preferences is crucial for this policy development. METHODS: Working with the Senegalese Government, a choice experiment (CE) was developed to elicit the job preferences of physicians and non-physicians. Attributes were defined using a novel mixed-methods approach, combining interviews and best-worst scaling (Case 1). Six attributes were categorised as 'individual (extrinsic) incentive' attributes ('type of contract', 'provision of training opportunities', 'provision of an allowance' and 'provision of accommodation') or 'functioning health system' attributes ('availability of basic equipment in health facilities' and 'provision of supportive supervision by health administrators'). Using face-to-face interviews, the CE was administered to 55 physicians (3909 observations) and 246 non-physicians (17 961 observations) randomly selected from those working in eight 'difficult' regions in Senegal. Conditional logit was used to analyse responses. This is the first CE to both explore the impact of contract type on rural retention and to estimate value of attributes in terms of willingness to stay (WTS) in current rural post. RESULTS: For both physicians and non-physicians, a permanent contract is the most important determinant of rural job retention, followed by availability of equipment and provision of training opportunities. Retention probabilities suggest that policy reform affecting only a single attribute is unlikely to encourage health professionals to remain in 'difficult' regions. The relative importance of an allowance is low; however, the level of such financial incentives requires further investigation. CONCLUSION: Contract type is a key factor impacting on retention. This has led the Senegalese Health Ministry to introduce a new rural assignment policy that recruits permanent staff from the pool of annually contracted healthcare professionals on the condition that they take up rural posts. While this is a useful policy development, further efforts to retain rural health workers, considering both personal incentives and the functioning of health systems, are necessary to ensure health worker numbers are adequate to meet the needs of rural communities.

Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study.

OBJECTIVE: To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF ß-amyloid (Aß) and tau. METHODS: Mixed-effects models of CSF Aß1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aß1-42 for up to 5 years. RESULTS: In subjects with biomarker-confirmed Alzheimer's pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aß1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aß1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aß deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aß from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aß over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aß levels to the average level of Alzheimer's subjects from 18.8 to 10.8 years. CONCLUSIONS: Iron might facilitate Aß deposition in Alzheimer's and accelerate the disease process.

Cerebral quantitative susceptibility mapping predicts amyloid-ß-related cognitive decline.

See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-ß by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-ß to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-ß load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-ß positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [ß(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [ß(standard error) = -0.139 (0.048), P = 0.004), and attention [ß(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [ß(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [ß(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-ß to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-ß positron emission tomography to stratify individuals at risk of decline.

Retention of qualified healthcare workers in rural Senegal: lessons learned from a qualitative study.

INTRODUCTION: Deployment and retention of a sufficient number of skilled and motivated human resources for health (HRH) at the right place and at the right time are critical to ensure people's right to access a universal quality of health care. Vision Tokyo 2010 Network, an international network of HRH managers at the ministry of health (MoH) level in nine Francophone African countries, identified maldistribution of a limited number of healthcare personnel and their retention in rural areas as overarching problems in the member countries. The network conducted this study in Senegal to identify the determining factors for the retention of qualified HRH in rural areas, and to explore an effective and feasible policy that the MoH could implement in the member countries. METHODS: Doctors, nurses, midwives and superior technicians in anesthesiology who were currently working (1) in a rural area and had been for more than 2 years, (2) in Dakar with experience of working in a rural area or (3) in Dakar without any prior experience working in a rural area were interviewed about their willingness and reasons for accepting work or continuing to work in a rural area and their suggested policies for deployment and retention of healthcare workers in rural areas. In-depth interviews were conducted with policy makers in MoH, asking for their perceptions on human resource management in health and about their suggested policies for deployment and retention. RESULTS: A total of 176 healthcare workers and eight policy makers were interviewed. The willingness to face challenges in a new place was one of the main reasons for accepting work in rural areas. The identified factors to motivate or demotivate healthcare workers in rural areas were related to pre-service and in-service education, regulatory systems, financial and non-financial incentive schemes and environmental support. Factors not included in WHO's global recommendation but highly valued in this study were (1) the fairness, transparency and predictability of human resource management by the MoH and (2) employment status, ie permanent government staff versus contract staff. Financial incentive schemes were less commonly suggested. Family bonding and religious-related non-financial incentive schemes were found to be specific factors in Senegal, but would also be applicable in countries where family and religion play important roles in the values of healthcare workers. CONCLUSIONS: Improved HRH management, eg the transparency of human resource management by the MoH, was identified as a pre-condition of any policy implementation related to HRH. This factor can be considered in other countries struggling to retain healthcare workers in rural areas. The Vision Tokyo 2010 Network or HRH managers' network in Francophone Africa, Senegal MoH and the research team plan to conduct a quantitative survey to confirm the generalizability of the results of this qualitative survey, and to identify the most effective combination of policies to improve the retention of qualified healthcare workers and seek their implementation in other countries in the region as network activities.

Trends in maternal and newborn health characteristics and obstetric interventions among Aboriginal and Torres Strait Islander mothers in Western Australia from 1986 to 2009.

BACKGROUND: Detailed analyses of long-term trends in Aboriginal maternal and newborn health characteristics are lacking. AIM: To examine trends in maternal and newborn health characteristics for all mothers who were recorded as Aboriginal in the Western Australian Midwives' Notification System from 1986 to 2009. MATERIALS AND METHODS: Births were categorised into four-year time intervals (1986-1989, 1990-1993, 1994-1997, 1998-2001, 2002-2005, 2006-2009). Trends in maternal demographic characteristics, pre-existing medical conditions, pregnancy complications and neonatal characteristics were examined. RESULTS: For 37 424 births recorded from 1986 to 2009, the proportion of births to mothers aged ≤19 years decreased (31-22%, P < 0.001) along with the prevalence of pre-eclampsia (6.8-4.0%, P < 0.001) and antepartum haemorrhage (4.8-3.2%, P < 0.001). There were increases in the prevalence of diabetes in pregnancy (3.8-6.6%, P < 0.001), induction of labour (17.8-21.4%, P < 0.001), elective caesarean (6.6-8.2%, P < 0.001) and emergency caesarean (9.5-14.9%, P < 0.001) deliveries. There were no changes in the overall prevalence of preterm births (15.4-15.9%, P = 0.32). However, increases were observed in the prevalence of medically indicated preterm births with and without prelabour rupture of membranes (1.0-1.7%; P < 0.001 and 3.3-4.3%; P = 0.005, respectively). There were no significant changes in the rates of smoking during pregnancy (51-52% from 1998 to 2009, P = 0.18), small-for-gestational age (16.9-17.2%, P = 0.07), suboptimal-birthweight (20.4-20.1%, P = 0.92), stillbirths (14.7 per 1000-12.1 per 1000, P = 0.22) and neonatal deaths (6.2 per 1000-5.5 per 1000, P = 0.68). CONCLUSION: Encouraging trends include reduced rates of teenage pregnancy, pre-eclampsia and antepartum haemorrhage. The persistent high rates of smoking during pregnancy, preterm births, stillbirths, neonatal deaths and increasing rates of diabetes in pregnancy are of concern.

Sero-epidemiological evaluation of Plasmodium falciparum malaria in Senegal.

BACKGROUND: In Senegal, a significant decrease of malaria transmission intensity has been noted the last years. Parasitaemia has become lower and, therefore, more difficult to detect by microscopy. In the context of submicroscopic parasitaemia, it has become relevant to rely on relevant malaria surveillance tools to better document malaria epidemiology in such settings. Serological markers have been proposed as an essential tool for malaria surveillance. This study aimed to evaluate the sero-epidemiological situation of Plasmodium falciparum malaria in two sentinel sites in Senegal. METHODS: Cross-sectional surveys were carried out in Velingara (south Senegal) and Keur Soce (central Senegal) between September and October 2010. Children under 10 years old, living in these areas, were enrolled using two-level, random sampling methods. P. falciparum infection was diagnosed using microscopy. P. falciparum antibodies against circumsporozoite protein (CSP), apical membrane protein (AMA1) and merozoite surface protein 1_42 (MSP1_42) were measured by ELISA method. A stepwise logistic regression analysis was done to assess factors associated with P. falciparum antibodies carriage. RESULTS: A total of 1,865 children under 10 years old were enrolled. The overall falciparum malaria prevalence was 4.99% with high prevalence in Velingara of 10.03% compared to Keur Soce of 0.3%. Symptomatic malaria cases (fever associated with parasitaemia) represented 17.37%. Seroprevalence of anti-AMA1, anti-MSP1_42 and anti-CSP antibody was 38.12, 41.55 and 40.38%, respectively. The seroprevalence was more important in Velingara and increased with age, active malaria infection and area of residence. CONCLUSION: The use of serological markers can contribute to improved malaria surveillance in areas with declining malaria transmission. This study provided useful baseline information about the sero-epidemiological situation of malaria in Senegal and can contribute to the identification of malaria hot spots in order to concentrate intervention efforts. TRIAL REGISTRATION NUMBER: PACTR201305000551876 ( http://www.pactr.org ).

Prevalence of gestational diabetes mellitus among Indigenous women and comparison with non-Indigenous Australian women: 1990-2009.

BACKGROUND: Evidence on long-term trends in gestational diabetes mellitus (GDM) prevalence in Australia is lacking. AIMS: To assess and compare trends in GDM prevalence among Indigenous and non-Indigenous Australian women. MATERIALS AND METHODS: Analysis of crude and age-adjusted GDM prevalence over time by Indigenous status and age, using routinely collected midwives data from Australian states and territories on mothers giving birth from 1990 to 2009. RESULTS: Despite considerable data variation, particularly in 1990-1999, and likely underestimation of GDM prevalence, crude and age-adjusted GDM prevalences were higher in Indigenous than non-Indigenous women at all time-points (4.7% vs 3.1% in 1990-1999; 5.1% vs 4.5% in 2000-2009, P < 0.0001). Data variability precluded quantitative assessment of trends and changes in prevalence ratios before 2000. From 2000 to 2009, GDM prevalence increased significantly among Indigenous women by a mean 2.6% annually (Ptrend <0.0001), and non-Indigenous women by 3.2% annually (Ptrend <0.0001), with no significant trend in the age-adjusted Indigenous/non-Indigenous prevalence ratios (PR) (P = 0.34). GDM prevalence increased significantly with age (P < 0.0001), although the increase with age was significantly greater among Indigenous women (PR 5.34 (4.94-5.77), ≥35 vs <25 years) compared to non-Indigenous women (PR 3.72 (3.64-3.81), ≥35 vs <25 years), Pinteraction <0.0001. CONCLUSIONS: Bearing data quality concerns in mind, GDM prevalence is increasing rapidly among Australian women, more than doubling in non-Indigenous women between 1990 and 2009. Prevalence is consistently higher in Indigenous versus non-Indigenous women, with statistically consistent differences between the groups in recent years. The marked increase in prevalence with age highlights an important period for prevention, particularly for Indigenous women.

Specific role of maternal weight change in the first trimester of pregnancy on birth size.

The specific role of weight change in the first weeks of gestation in fetal growth has not been fully explored in humans. Our aims were to investigate: (1) the specific association between weight change in the first trimester of pregnancy (WCT1) and size at birth in term pregnancies; and (2) the role of placental weight in this relationship. From 2002 women included in the French EDEN study, 1744 mother-child pairs reached term, had pre-pregnancy weight available and at least five measures of weight in pregnancy. We extrapolated women's weight at each week of gestation with a three-degree polynomial model and estimated weight change during each trimester of gestation. We used a multivariate linear model to investigate the associations between WCT1 and birth size after taking into account potential confounders (age, parity, BMI, tobacco use, educational level, length of gestation, newborn gender, weight change after the first trimester and centre of study). Then, we performed path analysis to investigate whether the relation between WCT1 and birth size could be mediated by placental weight. After taking into account weight gain in later gestation, WCT1 was positively associated with birthweight. Results of path analysis showed that there was no direct association between WCT1 and birth size, but that this association was mediated by placental weight. Weight change during the first weeks of pregnancy may impact on fetal growth independently of weight change later in pregnancy through its effects on placental growth and function.