Lessons learnt from the multi-centre LAparoscopic Versus Abdominal hysterectomy (LAVA) randomised controlled trial.

Background: The LAparoscopic Versus Abdominal hysterectomy (LAVA) randomised controlled trial comparing laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH) closed prematurely on the grounds of futility. Here we identify the challenges faced and lessons learnt. Objectives: To explore the views and experiences of clinical/research staff in order to understand how these might act as barriers to trial participation and recruitment. Materials and Methods: Review of the trial progress and collation of the views and experiences of clinical/ research staff on all aspects of the trial. Data were collected from transcribed conversations, email, phone, or video conferencing interactions and analysed descriptively. Main outcome measures: Site set-up milestones, recruitment rates and reasons provided by clinical/research staff for site's declining to participate. Opinions, preferences and experiences of clinicians/researchers and challenges to participation and recruitment. Results: The mean time from initial site contact to opening was 253 days and 68 days to randomise their first participant. 265 patients were screened from 13 sites over 13 months, 154 were eligible, and 75 (59%) were randomised. Of the 53 not randomised, 23 (43%) women preferred LH whilst 6 (11%) preferred AH. The main reasons given for failure to recruit or activate set-up in the 21 sites open or in set-up, were lack of research/ clinical capacity imposed by the COVID-19 pandemic and lack of clinician equipoise. Conclusions: The main reasons for the LAVA trial failure were lack of equipoise amongst surgeons and the adverse impact of the COVID-19 pandemic on clinical/research services. What is new?: Surgeons' preference for laparoscopic hysterectomy is not shared by most patients. Many patients prefer an open hysterectomy to a laparoscopic one.

Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

Association of Blood MicroRNA Expression and Polymorphisms with Cognitive and Biomarker Changes in Older Adults.

BACKGROUND: Identifying individuals before the onset of overt symptoms is key in the prevention of Alzheimer's disease (AD). OBJECTIVES: Investigate the use of miRNA as early blood-biomarker of cognitive decline in older adults. DESIGN: Cross-sectional. SETTING: Two observational cohorts (CHARIOT-PRO, Alzheimer's Disease Neuroimaging Initiative (ADNI)). PARTICIPANTS: 830 individuals without overt clinical symptoms from CHARIOT-PRO and 812 individuals from ADNI. MEASUREMENTS: qPCR analysis of a prioritised set of 38 miRNAs in the blood of individuals from CHARIOT-PRO, followed by a brain-specific functional enrichment analysis for the significant miRNAs. In ADNI, genetic association analysis for polymorphisms within the significant miRNAs' genes and CSF levels of phosphorylated-tau, total-tau, amyloid-ß42, soluble-TREM2 and BACE1 activity using whole genome sequencing data. Post-hoc analysis using multi-omics datasets. RESULTS: Six miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) were downregulated in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The pathway enrichment analysis indicated involvement of apoptosis and inflammation, relevant in early AD stages. Polymorphisms within genes encoding for hsa-miR-29c-3p and hsa-miR-146a-5p were associated with CSF levels of amyloid-ß42, soluble-TREM2 and BACE1 activity, and 21 variants were eQTL for hippocampal MIR29C expression. CONCLUSIONS: six miRNAs may serve as potential blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within these miRNAs suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.

Multimodal Precision Prevention - A New Direction in Alzheimer's Disease.

At least 40% of all dementia has been linked to modifiable risk factors suggesting a clear potential for preventative approaches targeting these factors. Despite the recent promising findings from anti-amyloid monoclonal antibodies, a limited proportion of patients are expected to be eligible for these novel AD treatments. Given the heterogeneous nature of AD and the complex multi-level pathological processes leading to dementia (involving, e.g., shared risk factors, interaction of different pathology mechanisms, and their putative synergistic effects on cognition), targeting a single pathology may not be sufficient to halt or significantly impact disease progression. With exponentially increasing numbers of patients world-wide, in parallel to the unprecedented population ageing, new multimodal therapy approaches targeting several modifiable risk factors and disease mechanisms simultaneously are urgently required. Developing the next generation of combination therapies with lifestyle intervention and pharmacological treatments, implementing the right interventions for the right people at the right time, and defining accessible and sustainable strategies worldwide are crucial. Here, we summarize the state-of-the-art multimodal lifestyle-based approaches, especially findings and lessons learned from the FINGER trial, for prevention and risk reduction of cognitive impairment and dementia. We also discuss some emerging underlying biological mechanisms and the current development of precision prevention approaches. We present an example of a novel trial design combining healthy lifestyle changes with a repurposed putative disease-modifying drug and place this study in the context of the World-Wide FINGERS, the first interdisciplinary network of multimodal trials dedicated to the prevention and risk reduction of cognitive impairment and dementia.

Feasibility and preliminary efficacy of the LEAD trial: a cluster randomized controlled lifestyle intervention to improve hippocampal volume in older adults at-risk for dementia.

BACKGROUND: Healthy diet and exercise are associated with reduced risk of dementia in older adults. The impact of diet and exercise interventions on brain health is less consistent, especially with dietary interventions which rely on varying approaches. Our objective was to evaluate the feasibility and preliminary efficacy of a 6-month intervention combining exercise with a novel dietary counseling approach to improve hippocampal volume among older adults at-risk for dementia. METHODS: Participants with vascular risk factors and subjective cognitive decline or early mild cognitive impairment were cluster randomized in groups of 3-4 to the diet intervention (DIET) or control education (ED) group. All participants engaged in 1 h of supervised exercise per week and additional exercise at home. DIET involved 1 h per week of group-based dietary counseling comprising education, goal setting, and strategy training. ED involved 1 h per week of group-based brain health education classes. Our primary outcome was change in hippocampal volume from baseline to 6 months. Secondary outcomes included changes in cognitive function, blood biomarkers, diet, and fitness. Recruitment challenges and early discontinuation of the trial due to COVID-19 necessitated a revised focus on feasibility and preliminary efficacy. RESULTS: Of 190 older adults contacted, 14 (7%) were eligible and enrolled, constituting 21% of our recruitment target. All participants completed the intervention and attended 90% of exercise and DIET/ED sessions on average. All 6-month assessments prior to COVID-19 were completed but disruptions to in-person testing resulted in incomplete data collection. No serious adverse events occurred and all participants expressed positive feedback about the study. Preliminary findings did not identify any significant changes in hippocampal volume; however, substantial improvements in diet and HbA1c were observed with DIET compared to ED (d = 1.75 and 1.07, respectively). CONCLUSIONS: High adherence and retention rates were observed among participants and preliminary findings illustrate improvements in diet quality and HbA1c. These results indicate that a larger trial is feasible if difficulties surrounding recruitment can be mitigated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03056508 .

Blood Derived Amyloid Biomarkers for Alzheimer's Disease Prevention.

BACKGROUND: Reliable, widely accessible and affordable biomarkers for predicting Alzheimer's disease (AD) brain pathology status are a necessity to aid development of prevention strategies in cognitively healthy at-risk older adults, at the right timepoint. Measurements of the key neuropathological hallmark beta-amyloid (Aß) by PET neuroimaging or cerebrospinal fluid measures reflect its accumulation in the brain, yet recent methodological advancements now enable blood-based measures reflecting cerebral amyloid burden. OBJECTIVES: The current study validated the capacity of plasma Aß42/Aß40 measured using six different assays to predict amyloid positivity in a subgroup of cognitively unimpaired (CU) participants in the ADNI study and assessed its ability to discriminate CU from AD cases. We also explored economic viability of using two different plasma amyloid assays for pre-screening in AD prevention trials and as routine clinical diagnostic tool, versus amyloid PET alone. DESIGN: A cross-sectional analysis of plasma and brain amyloid data, including comparative cost analysis of the plasma biomarkers in relation to brain amyloid PET. SETTING: Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS: ADNI participants consisting of 115 CU, mild cognitive impairment and AD cases who had plasma Aß42/Aß40 measured with six platforms. MEASUREMENTS: Plasma Aß42/Aß40 was measured via six different platforms: three immunoassays (Roche, Quanterix and ADx Neurosciences) and three mass spectrometry (MS) based assays (WashU, Shimadzu and Gothenburg). Aß-PET imaging was conducted within three months of plasma sampling using [18F]florbetapir. RESULTS: There was a weak to moderate correlation of plasma Aß42/Aß40 ratio between platforms. The MS-based WashU test had the highest capacity to discriminate between CU and AD (area under the curve, AUC = 0.734, 95% CI: 0.613-0.854; P = 0.008). Within the CU group, the WashU plasma amyloid test had the best discriminative capacity to distinguish Aß+ from Aß- (AUC = 0.753, 95% CI: 0.601-0.905; P = 0.003) closely followed by the immunoassay from Roche (AUC = 0.737, 95% CI: 0.597-0.877; P = 0.006). The exploratory economic analyses showed that the use of Roche or WashU plasma amyloid assay as a pre-screening tool prior to Aß-PET scans for clinical trial recruitment significantly reduced total screening cost (saving up to $5882 per recruited patient) expected in an AD prevention trial. CONCLUSIONS: With few available treatment strategies, dementia prevention is a global priority. CU individuals at risk for AD are the target population for dementia prevention but have been poorly studied. Our findings confirming diagnostic value of ultrasensitive immunoassays and high-performance immunoprecipitation coupled with MS for measurement of plasma Aß42/Aß40 to detect PET amyloid positivity in CU participants allude to potential clinical utility of this biomarker. Plasma Aß42/Aß40 could be optimal for pre-selecting at-risk candidates for more invasive and expensive investigations across AD prevention clinical trials and clinical care for a rapidly ageing population.

Associations of Cardiovascular and Non-Cardiovascular Comorbidities with Dementia Risk in Patients with Diabetes: Results from a Large UK Cohort Study.

BACKGROUND: Type 2 diabetes (T2D) is an established risk factor for dementia. However, it remains unclear whether the presence of comorbidities could further increase dementia risk in diabetes patients. OBJECTIVES: To examine the associations between cardiovascular and non-cardiovascular comorbidities and dementia risk in T2D patients. DESIGN: Population-based cohort study. SETTING: The UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: 489,205 T2D patients aged over 50 years in the UK CPRD. MEASUREMENTS: Major cardiovascular and non-cardiovascular comorbidities were extracted as time-varying exposure variables. The outcome event was dementia incidence based on dementia diagnosis or dementia-specific drug prescription. RESULTS: During a median of six years follow-up, 33,773 (6.9%) incident dementia cases were observed. Time-varying Cox regressions showed T2D patients with stroke, peripheral vascular disease, atrial fibrillation, heart failure or hypertension were at higher risk of dementia compared to those without such comorbidities (HR [95% CI] = 1.64 [1.59-1.68], 1.37 [1.34-1.41], 1.26 [1.22-1.30], 1.15 [1.11-1.20] or 1.10 [1.03-1.18], respectively). Presence of chronic obstructive pulmonary disease or chronic kidney disease was also associated with increased dementia risk (HR [95% CI] = 1.05 [1.01-1.10] or 1.11 [1.07-1.14]). CONCLUSIONS: A range of cardiovascular and non-cardiovascular comorbidities were associated with further increases of dementia risk in T2D patients. Prevention and effective management of these comorbidities may play a significant role in maintaining cognitive health in T2D patients.

Evidence-Based Tools for Dietary Assessments in Nutrition Epidemiology Studies for Dementia Prevention.

Increasing evidence proposes diet as a notable modifiable factor and viable target for the reduction of Alzheimer's Disease risk and age-related cognitive decline. However, assessment of dietary exposures is challenged by dietary capture methods that are prone to misreporting and measurement errors. The utility of -omics technologies for the evaluation of dietary exposures has the potential to improve reliability and offer new insights to pre-disease indicators and preventive targets in cognitive aging and dementia. In this review, we present a focused overview of metabolomics as a validation tool and framework for investigating the immediate or cumulative effects of diet on cognitive health.

At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer's Disease and Related Research.

Neuroimaging serves a variety of purposes in Alzheimer's disease (AD) and related dementias (ADRD) research - from measuring microscale neural activity at the subcellular level, to broad topological patterns seen across macroscale-brain networks, and everything in between. In vivo imaging provides insight into the brain's structure, function, and molecular architecture across numerous scales of resolution; allowing examination of the morphological, functional, and pathological changes that occurs in patients across different AD stages (1). AD is a complex and potentially heterogenous disease, with no proven cure and no single risk factor to isolate and measure, whilst known risk factors do not fully account for the risk of developing this disease (2). Since the 1990's, technological advancements in neuroimaging have allowed us to visualise the wide organisational structure of the brain (3) and later developments led to capturing information of brain 'functionality', as well as the visualisation and measurement of the aggregation and accumulation of AD-related pathology. Thus, in vivo brain imaging has and will continue to be an instrumental tool in clinical research, mainly in the pre-clinical disease stages, aimed at elucidating the biological complex processes and interactions underpinning the onset and progression of cognitive decline and dementia. The growing societal burden of AD/ADRD means that there has never been a greater need, nor a better time, to use such powerful and sensitive tools to aid our understanding of this undoubtedly complex disease. It is by consolidating and reflecting on these imaging advancements and developing long-term strategies across different disciplines, that we can move closer to our goal of dementia prevention. This short commentary will outline recent developments in neuroimaging in the field of AD and dementia by first describing the historical context of AD classification and the introduction of AD imaging biomarkers, followed by some examples of significant recent developments in neuroimaging methods and technologies.

Interim data monitoring in cluster randomised trials: Practical issues and a case study.

BACKGROUND: There is an abundance of guidance for the interim monitoring of individually randomised trials. While methodological literature exists on how to extend these methods to cluster randomised trials, there is little guidance on practical implementation. Cluster trials have many features which make their monitoring needs different. We outline the methodological and practical challenges of interim monitoring of cluster trials; and apply these considerations to a case study. CASE STUDY: The E-MOTIVE study is an 80-cluster randomised trial of a bundle of interventions to treat postpartum haemorrhage. The proposed data monitoring plan includes (1) monitor sample size assumptions, (2) monitor for evidence of selection bias, and (3) an interim assessment of the primary outcome, as well as monitoring data completeness. The timing of the sample size monitoring is chosen with both consideration of statistical precision and to allow time to recruit more clusters. Monitoring for selection bias involves comparing individual-level characteristics and numbers recruited between study arms to identify any post-randomisation participant identification bias. An interim analysis of outcomes presented with 99.9% confidence intervals using the Haybittle-Peto approach should mitigate any concern regarding the inflation of type-I error. The pragmatic nature of the trial means monitoring for adherence is not relevant, as it is built into a process evaluation. CONCLUSIONS: The interim analyses of cluster trials have a number of important differences to monitoring individually randomised trials. In cluster trials, there will often be a greater need to monitor nuisance parameters, yet there will often be considerable uncertainty in their estimation. This means the utility of sample size re-estimation can be questionable particularly when there are practical or funding difficulties associated with making any changes to planned sample sizes. Perhaps most importantly interim monitoring has the potential to identify selection bias, particularly in trials with post-randomisation identification or recruitment. Finally, the pragmatic nature of cluster trials might mean that the utility of methods to allow for interim monitoring of outcomes based on statistical testing, or monitoring for adherence to study interventions, are less relevant. Our intention is to facilitate the planning of future cluster randomised trials and to promote discussion and debate to improve monitoring of these studies.

Uterine artery embolisation or myomectomy for women with uterine fibroids wishing to avoid hysterectomy: a cost-utility analysis of the FEMME trial.

OBJECTIVES: To assess the cost-effectiveness of uterine artery embolisation (UAE) and myomectomy for women with symptomatic uterine fibroids wishing to avoid hysterectomy. DESIGN: Economic evaluation alongside the FEMME randomised controlled trial. SETTING: 29 UK hospitals. POPULATION: Premenopausal women who had symptomatic uterine fibroids amenable to UAE or myomectomy wishing to avoid hysterectomy. 254 women were randomised to UAE (127) and myomectomy (127). METHODS: A within-trial cost-utility analysis was conducted from the perspective of the UK NHS. MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs) measured using the EuroQoL EQ-5D-3L, combined with costs to estimate cost-effectiveness over 2 and 4 years of follow-up. RESULTS: Over a 2-year time horizon, UAE was associated with higher mean costs (difference £645; 95% CI -1381 to 2580) and lower QALYs (difference -0.09; 95% CI -0.11 to -0.04) when compared with myomectomy. Similar results were observed over the 4-year time horizon. Thus, UAE was dominated by myomectomy. Results of the sensitivity analyses were consistent with the base case results for both years. Over 2 years, UAE was associated with higher costs (difference £456; 95% CI -1823 to 3164) and lower QALYs (difference -0.06; 95% CI -0.11 to -0.02). CONCLUSIONS: Myomectomy is a cost-effective option for the treatment of uterine fibroids. The differences in costs and QALYs are small. Women should be fully informed and have the option to choose between the two procedures. TWEETABLE ABSTRACT: Fully informed women with uterine fibroids should have a choice between uterine artery embolisation or myomectomy.

Vitamin B12 and Folate Status in Cognitively Healthy Older Adults and Associations with Cognitive Performance.

OBJECTIVES: To determine prevalence of vitamin B12 and folate deficiency and associations with cognitive performance in participants recruited for the Cognitive Health in Ageing Register: Investigational, Observational, and Trial Studies in Dementia Research: Prospective Readiness cOhort Study (CHARIOTPRO) SubStudy (CPRO-SS). DESIGN: Cross-sectional analysis of data collected in the screening phase for the CPRO-SS. SETTING: Participants were recruited from the Chariot Register at Imperial College London comprising approximately 39,000 community dwelling volunteers. PARTICIPANTS: Community dwelling individuals aged 60-85 years with B vitamin biomarker measures available were included (n=1946). After medical history and other exclusions, 1347 cognitively healthy participants were included for analysis of cognitive data. MEASUREMENTS: Cognitive status was assessed with the Repeatable Battery for Neuropsychological Status (RBANS). Assays included vitamin B12 and folate, followed by serum methylmalonic acid and homocysteine levels for those with low vitamin B12. Gender-specific linear regression analysis was performed for associations between cognition and biomarkers. Non-gender specific regression for groups graded by B vitamin deficiency severity were also performed. RESULTS: Vitamin B12 deficiency (<148pmol/L) was found in 17.2% of individuals and folate deficiency (<10nmol/L) in 1% of our participants. Low vitamin B12 was associated with poorer memory (p<0.03) in men. A high BMI predicted poorer attention and visuospatial indices (p<0.05). A regression analysis by B12 level revealed associations with poorer attention (ß -6.46; p=0.004) for the deficient group and with immediate memory (ß -2.99; p=0.019) for those categorised as severely deficient. CONCLUSION: Older men and women are prone to vitamin B12 deficiency with associated subtle and different domain-specific disruptive effects in measures of memory and attention. Elevated homocysteine and methylmalonic acid contributed to poorer cognitive performance. Novel groups at particular risk of cognitive deficit were identified for future interventional studies in this field.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial.

OBJECTIVE: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. DESIGN: Blinded (clinician and participant), proof of principle, placebo-controlled trial. SETTING: Fifteen UK maternity units. POPULATION: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24+0 -31+6  weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. PRIMARY OUTCOME: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. RESULTS: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI -1175 to 592; P = 0.5), and over days 1-14 was 48 pg/ml (95% CI -1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50-1.40; P = 0.6). The median time from randomisation to childbirth was 9 days (interquartile range [IQR] 5-14 days) for the pravastatin group and 7 days (IQR 4-11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. CONCLUSIONS: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. TWEETABLE ABSTRACT: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds.

Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.

BACKGROUND: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). OBJECTIVES: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. DESIGN: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. RESULTS: 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.

Evidence of factors influencing self-medication with antibiotics in low and middle-income countries: a systematic scoping review.

OBJECTIVES: Self-medication with antibiotics (SMA) is a practice of global concern with a higher incidence within the low- and middle-income countries (LMICs). Despite worldwide efforts to control and promote the rational use of antibiotics, the continuing practice of SMA systematically exposes individuals and communities to the risk of antibiotic resistance and a host of other antibiotic side-effects. This systematic scoping review maps evidence on the factors influencing SMA in these settings. STUDY DESIGN: Systematic scoping review. METHODS: The search strategy involved electronic databases including PubMed, Web of science, Science Direct, EBSCOhost, Google Scholar, BioMed Central, and the World Health Organization Library. PRISMA P guidelines and Arksey and O'Malley's framework were used. Thematic analysis was used to identify the factors that influence the practices of SMA in LMICs. The Mixed Method Appraisal Tool (MMAT), version 2011, was used to assess the quality of the included primary studies. RESULTS: Fifteen studies met the inclusion criteria. Studies included participants from the following LMICs: Guatemala, India, Indonesia, Kenya, Laos, Nepal, Nigeria, Pakistan, Sri Lanka, and Yemen. The findings of the review emphasized a considerable high prevalence of SMA, ranging from 8.1% to 93%, with an association with the level of education, monthly income, and gender of participants. Accessibility, affordability, and conditions of health facilities, as well as the health-seeking behavior, are factors that influence SMA in LMICs. Health conditions such as a sore throat, common cold, cough, headache, toothache, flu-like symptoms, pain relief, fever, runny nose, toothache, upper respiratory tract infections, and urinary tract infection were the major complaints that led to the practices of SMA. CONCLUSIONS: There is a considerable level of research evidence predominantly in some LMICs from Asia, with less evidence from African LMICs. Sociocultural determinants of health associated with the structure and conditions of health system as well as the health-seeking behavior are the main factors influencing SMA. Contextual and comprehensive studies on the factors influencing the non-prescribed use of antibiotics are needed to enable evidence-based strategies to correctly address the utilization of antibiotics and contain the problem of antimicrobial resistance, especially within the LMICs. PROSPERO REGISTRATION: CRD42017072954.