An Approach for Generating Realistic Australian Synthetic Healthcare Data.

Healthcare data is a scarce resource and access is often cumbersome. While medical software development would benefit from real datasets, the privacy of the patients is held at a higher priority. Realistic synthetic healthcare data can fill this gap by providing a dataset for quality control while at the same time preserving the patient's anonymity and privacy. Existing methods focus on American or European patient healthcare data but none is exclusively focused on the Australian population. Australia is a highly diverse country that has a unique healthcare system. To overcome this problem, we used a popular publicly available tool, Synthea, to generate disease progressions based on the Australian population. With this approach, we were able to generate 100,000 patients following Queensland (Australia) demographics.

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.

Bias-Corrected CMIP5 Projections for Climate Change and Assessments of Impact on Malaria in Senegal under the VECTRI Model.

On the climate-health issue, studies have already attempted to understand the influence of climate change on the transmission of malaria. Extreme weather events such as floods, droughts, or heat waves can alter the course and distribution of malaria. This study aims to understand the impact of future climate change on malaria transmission using, for the first time in Senegal, the ICTP's community-based vector-borne disease model, TRIeste (VECTRI). This biological model is a dynamic mathematical model for the study of malaria transmission that considers the impact of climate and population variability. A new approach for VECTRI input parameters was also used. A bias correction technique, the cumulative distribution function transform (CDF-t) method, was applied to climate simulations to remove systematic biases in the Coupled Model Intercomparison Project Phase 5 (CMIP5) global climate models (GCMs) that could alter impact predictions. Beforehand, we use reference data for validation such as CPC global unified gauge-based analysis of daily precipitation (CPC for Climate Prediction Center), ERA5-land reanalysis, Climate Hazards InfraRed Precipitation with Station data (CHIRPS), and African Rainfall Climatology 2.0 (ARC2). The results were analyzed for two CMIP5 scenarios for the different time periods: assessment: 1983-2005; near future: 2006-2028; medium term: 2030-2052; and far future: 2077-2099). The validation results show that the models reproduce the annual cycle well. Except for the IPSL-CM5B model, which gives a peak in August, all the other models (ACCESS1-3, CanESM2, CSIRO, CMCC-CM, CMCC-CMS, CNRM-CM5, GFDL-CM3, GFDL-ESM2G, GFDL-ESM2M, inmcm4, and IPSL-CM5B) agree with the validation data on a maximum peak in September with a period of strong transmission in August-October. With spatial variation, the CMIP5 model simulations show more of a difference in the number of malaria cases between the south and the north. Malaria transmission is much higher in the south than in the north. However, the results predicted by the models on the occurrence of malaria by 2100 show differences between the RCP8.5 scenario, considered a high emission scenario, and the RCP4.5 scenario, considered an intermediate mitigation scenario. The CanESM2, CMCC-CM, CMCC-CMS, inmcm4, and IPSL-CM5B models predict decreases with the RCP4.5 scenario. However, ACCESS1-3, CSIRO, NRCM-CM5, GFDL-CM3, GFDL-ESM2G, and GFDL-ESM2M predict increases in malaria under all scenarios (RCP4.5 and RCP8.5). The projected decrease in malaria in the future with these models is much more visible in the RCP8.5 scenario. The results of this study are of paramount importance in the climate-health field. These results will assist in decision-making and will allow for the establishment of preventive surveillance systems for local climate-sensitive diseases, including malaria, in the targeted regions of Senegal.

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.

Malaria in Senegal: Recent and Future Changes Based on Bias-Corrected CMIP6 Simulations.

Malaria is a constant reminder of the climate change impacts on health. Many studies have investigated the influence of climatic parameters on aspects of malaria transmission. Climate conditions can modulate malaria transmission through increased temperature, which reduces the duration of the parasite's reproductive cycle inside the mosquito. The rainfall intensity and frequency modulate the mosquito population's development intensity. In this study, the Liverpool Malaria Model (LMM) was used to simulate the spatiotemporal variation of malaria incidence in Senegal. The simulations were based on the WATCH Forcing Data applied to ERA-Interim data (WFDEI) used as a point of reference, and the biased-corrected CMIP6 model data, separating historical simulations and future projections for three Shared Socio-economic Pathways scenarios (SSP126, SSP245, and SSP585). Our results highlight a strong increase in temperatures, especially within eastern Senegal under the SSP245 but more notably for the SSP585 scenario. The ability of the LMM model to simulate the seasonality of malaria incidence was assessed for the historical simulations. The model revealed a period of high malaria transmission between September and November with a maximum reached in October, and malaria results for historical and future trends revealed how malaria transmission will change. Results indicate a decrease in malaria incidence in certain regions of the country for the far future and the extreme scenario. This study is important for the planning, prioritization, and implementation of malaria control activities in Senegal.

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.

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.

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.

Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study.

BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (ß = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (ß = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (ß = - 0.5, 95% CI -0.6 to 0.4) and 18 years (ß = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (ß = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

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.

Impact of different heat wave definitions on daily mortality in Bandafassi, Senegal.

OBJECTIVE: The aim of this study is to find the most suitable heat wave definition among 15 different ones and to evaluate its impact on total, age-, and gender-specific mortality for Bandafassi, Senegal. METHODS: Daily weather station data were obtained from Kedougou situated at 17 km from Bandafassi from 1973 to 2012. Poisson generalized additive model (GAM) and distributed lag non-linear model (DLNM) are used to investigate the effect of heat wave on mortality and to evaluate the nonlinear association of heat wave definitions at different lag days, respectively. RESULTS: Heat wave definitions, based on three or more consecutive days with both daily minimum and maximum temperatures greater than the 90th percentile, provided the best model fit. A statistically significant increase in the relative risk (RRs 1.4 (95% Confidence Interval (CI): 1.2-1.6), 1.7 (95% CI: 1.5-1.9), 1.21 (95% CI: 1.08-1.3), 1.2 (95% CI: 1.04-1.5), 1.5 (95% CI: 1.3-1.8), 1.4 (95% CI: 1.2-1.5), 1.5 (95% CI: 1.07-1.6), and 1.5 (95% CI: 1.3-1.8)) of total mortality was observed for eight definitions. By using the definition based on the 90th percentile of minimum and maximum temperature with a 3-day duration, we also found that females and people aged ≥ 55 years old were at higher risks than males and other different age groups to heat wave related mortality. CONCLUSION: The impact of heat waves was associated with total-, age-, gender-mortality. These results are expected to be useful for decision makers who conceive of public health policies in Senegal and elsewhere. Climate parameters, including temperatures and humidity, could be used to forecast heat wave risks as an early warning system in the area where we conduct this research. More broadly, our findings should be highly beneficial to climate services, researchers, clinicians, end-users and decision-makers.

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.

Acute phase markers in CSF reveal inflammatory changes in Alzheimer's disease that intersect with pathology, APOE ε4, sex and age.

It is unknown how neuroinflammation may feature in the etiology of Alzheimer's disease (AD). We profiled acute phase response (APR) proteins (α1-antitrypsin, α1-antichymotrypsin, ceruloplasmin, complement C3, ferritin, α-fibrinogen, ß-fibrinogen, γ-fibrinogen, haptoglobin, hemopexin) in CSF of 1291 subjects along the clinical and biomarker spectrum of AD to investigate the association between inflammatory changes, disease outcomes, and demographic variables. Subjects were stratified by Aß42/t-tau as well as the following clinical diagnoses: cognitively normal (CN); subjective cognitive decline (SCD); mild cognitive impairment (MCI); and AD dementia. In separate multiple regressions (adjusting for diagnosis, age, sex, APOE-ε4) of each APR protein and a composite of all APR proteins, CSF Aß42/t-tau status was associated with elevated ferritin, but not any other APR protein in CN and SCD subjects. Rather, the APR was elevated along with symptomatic progression (CN < SCD < MCI < AD), and this was elevation was mediated by CSF p-tau181. APOE ε4 status did not affect levels of any APR proteins in CSF, while these were elevated in males and with increased age. The performance of the APR in predicting clinical diagnosis was influenced by APOE ε4 status, sex, and age. These data provide new insight into inflammatory changes in AD and how this intersects with pathology changes and patient demographics.

Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.

OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. METHODS: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). CONCLUSION: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.

Drivers of stunting reduction in Senegal: a country case study.

BACKGROUND: Senegal has been an exemplar country in the West African region, reducing child stunting prevalence by 17.9% from 1992 to 2017. OBJECTIVES: In this study, we aimed to conduct a systematic in-depth assessment of factors at the national, community, household, and individual levels to determine the key enablers of Senegal's success in reducing stunting in children <5 y old between 1992/93 and 2017. METHODS: A mixed methods approach was implemented, comprising quantitative data analysis, a systematic literature review, creation of a timeline of nutrition-related programs, and qualitative interviews with national and regional stakeholders and mothers in communities. Demographic and Health Surveys and Multiple Indicator Cluster Surveys were used to explore stunting inequalities and factors related to the change in height-for-age z-score (HAZ) using difference-in-difference linear regression and the Oaxaca-Blinder decomposition method. RESULTS: Population-wide gains in average child HAZ and stunting prevalence have occurred from 1992/93 to 2017. Stunting prevalence reduction varied by geographical region and prevalence gaps were reduced slightly between wealth quintiles, maternal education groups, and urban compared with rural residence. Statistical determinants of change included improvements in maternal and newborn health (27.8%), economic improvement (19.5%), increases in parental education (14.9%), and better piped water access (8.1%). Key effective nutrition programs used a community-based approach, including the Community Nutrition Program and the Nutrition Enhancement Program. Stakeholders felt sustained political will and multisectoral collaboration along with improvements in poverty, women's education, hygiene practices, and accessibility to health services at the community level reduced the burden of stunting. CONCLUSIONS: Senegal's success in the stunting decline is largely attributed to the country's political stability, the government's prioritization of nutrition and execution of nutrition efforts using a multisectoral approach, improvements in the availability of health services and maternal education, access to piped water and sanitation facilities, and poverty reduction. Further efforts in the health, water and sanitation, and agriculture sectors will support continued success.

Climate Variability and Malaria over West Africa.

Malaria is a major public health problem in West Africa. Previous studies have shown that climate variability significantly affects malaria transmission. The lack of continuous observed weather station data and the absence of surveillance data for malaria over long periods have led to the use of reanalysis data to drive malaria models. In this study, we use the Liverpool Malaria Model (LMM) to simulate spatiotemporal variability of malaria in West Africa using daily rainfall and temperature from the following: Twentieth Century Reanalysis (20th CR), National Center for Environmental Prediction (NCEP), European Centre for Medium-Range Weather Forecasts (ECMWF) Atmospheric Reanalysis of the Twentieth Century (ERA20C), and interim ECMWF Re-Analysis (ERA-Interim). Malaria case data from the national surveillance program in Senegal are used for model validation between 2001 and 2016. The warm temperatures found over the Sahelian fringe of West Africa can lead to high malaria transmission during wet years. The rainfall season peaks in July to September over West Africa and Senegal, and the malaria season lasts from September to November, about 1-2 months after the rainfall peak. The long-term trends exhibit interannual and decadal variabilities. The LMM shows acceptable performance in simulating the spatial distribution of malaria incidence. However, some discrepancies are found. These results are useful for decision-makers who plan public health and control measures in affected West African countries. The study would have substantial implications for directing malaria surveillance activities and health policy. In addition, this malaria modeling framework could lead to the development of an early warning system for malaria in West Africa.

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.