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.

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.

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.

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.

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.

Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.

Background: Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part I, a retrospective joint analysis of cases diagnosed during a 20-year period. Methods: Patients with follow-up and tumor samples, treated between 1990 and 2010, in 93 centers/9 countries. Samples were centrally analyzed in three laboratories (the United Kingdom, the Netherlands and the United States). Results: Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001 and 2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% estrogen receptor (ER)-positive; 81.9% progesterone receptor (PR)-positive; 96.9% androgen receptor (AR)-positive [ER, PR or AR Allred score ≥3]; 61.1% Ki67 expression low (<14% positive cells); using immunohistochemistry (IHC) surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0.0-23.8) for all, 7.2 years (0.0-23.2), for M0, 2.6 years (0.0-12.7) for M1 patients. A significant improvement over time was observed in age-corrected BC mortality. BC-specific-mortality was higher for men younger than 50 years. Better overall (OS) and recurrence-free survival (RFS) were observed for highly ER+ (P = 0.001), highly PR+ (P = 0.002), highly AR+ disease (P = 0.019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade. Conclusions: Male BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in >90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.

Ultrasound bladder wall thickness and detrusor overactivity: a multicentre test accuracy study.

OBJECTIVE: Women with overactive bladder (OAB) often undergo urodynamics before invasive treatments are considered. Ultrasound measurement of bladder wall thickness (BWT) is a less invasive, less expensive and widely available test. It has the potential to diagnose the presence of detrusor overactivity (DO). We aimed to evaluate the accuracy of BWT in the diagnosis of DO. DESIGN: Prospective cohort study. SETTING: Twenty-two UK clinics (university and district general hospitals). METHODS: Consecutive eligible women with OAB symptoms had transvaginal ultrasound to estimate BWT (index test). The reference standard for the diagnosis of DO was urodynamic testing with multichannel subtracted cystometry. MAIN OUTCOME MEASURES: The sensitivity, specificity and likelihood ratios using a BWT threshold of ≥5 mm were used to indicate the presence of DO, and the area under the receiver operating characteristics (ROC) curve to give an overall estimate of BWT accuracy. RESULTS: Between March 2011 and 2013, 644/687 (94%) women recruited had both tests. The mean age was 52.7 years (standard deviation 13.9) and DO was diagnosed in 399/666 (60%) women. BWT had a sensitivity of 43% [95% confidence interval (CI) 38-48%], specificity of 62% (95% CI 55-68%), and likelihood ratios of 1.11 (95% CI 0.92-1.35) and 0.93 (95% CI 0.82-1.06) for positive and negative tests, respectively. The area under the ROC curve was 0.53 (95% CI 0.48-0.57). Extensive sensitivity analyses and subgroup analyses were carried out, but did not alter the interpretation. CONCLUSIONS: BWT is not a good replacement test for urodynamics in women with overactive bladder. TWEETABLE ABSTRACT: Bladder wall thickness is not a good replacement test for urodynamics in women with overactive bladder.

Cortical Lewy bodies and Aß burden are associated with prevalence and timing of dementia in Lewy body diseases.

AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aß plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aß plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aß plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.

An economic evaluation of outpatient versus inpatient polyp treatment for abnormal uterine bleeding.

OBJECTIVES: To undertake a cost-effectiveness analysis of outpatient uterine polypectomy compared with standard inpatient treatment under general anaesthesia. DESIGN: Economic evaluation carried out alongside the multi-centre, pragmatic, non-inferiority, randomised controlled Outpatient Polyp Treatment (OPT) trial. The UK National Health Service (NHS) perspective was used in the estimation of costs and the interpretation of results. SETTING: Thirty-one secondary care UK NHS hospitals between April 2008 and July 2011. PARTICIPANTS: Five hundred and seven women with abnormal uterine bleeding and hysteroscopically diagnosed endometrial polyps. INTERVENTIONS: Outpatient uterine polypectomy versus standard inpatient treatment. Clinicians were free to choose the technique for polypectomy within the allocated setting. MAIN OUTCOME MEASURES: Patient-reported effectiveness of the procedure determined by the women's self-assessment of bleeding at 6 months, and QALY gains at 6 and 12 months. RESULTS: Inpatient treatment was slightly more effective but more expensive than outpatient treatment, resulting in relatively high incremental cost-effectiveness ratios. Intention-to-treat analysis of the base case at 6 months revealed that it cost an additional £9421 per successfully treated patient in the inpatient group and £ 1,099,167 per additional QALY gained, when compared with outpatient treatment. At 12 months, these costs were £22,293 per additional effectively treated patient and £445,867 per additional QALY gained, respectively. CONCLUSIONS: Outpatient treatment of uterine polyps associated with abnormal uterine bleeding appears to be more cost-effective than inpatient treatment at willingness-to-pay thresholds acceptable to the NHS. TWEETABLE ABSTRACT: HTA-funded OPT trial concluded that outpatient uterine polypectomy is cost-effective compared with inpatient polypectomy.

Outcome in fetal lower urinary tract obstruction: a prospective registry study.

OBJECTIVE: To describe influences on decision-making and prognostic variables in the prenatal management of fetal lower urinary tract obstruction (LUTO). METHODS: This was a prospective registry study of pregnant women with a male fetus with LUTO from centers within the British Isles and The Netherlands. Women and/or their clinicians were given the treatment option of either conservative management or vesicoamniotic shunting (VAS). Baseline characteristics of women in the registry, reasons for entry to the registry and pregnancy outcomes were assessed. The main study outcomes were survival to 28 days after delivery, further survival to 2 years and renal function. Logistic regression analysis was used to examine prognostic variables that affected outcome. Results were compared with those of women in a randomized controlled trial (RCT) who were allocated randomly to a treatment option. RESULTS: Forty-five women were registered, of whom 78% (35/45) underwent conservative management. Twenty-seven women entered the registry owing to their clinician's preference for management and 18 because of their own preference. Compared to the conservative-management group of the RCT, a higher proportion of women in the registry opting for conservative management had a normal amniotic fluid volume at diagnosis (P = 0.05) and a diagnosis of LUTO ≥ 24 weeks' gestation (P = 0.003). On multivariable logistic regression analysis, these variables showed a significant association with perinatal survival (P < 0.001). Survival to 28 days after delivery was higher in the conservative-management group, at 69% (24/35), compared to 40% (4/10) in the VAS group (P = 0.02) but this difference had limited statistical significance owing to small study size (relative risk, 0.58 (95% CI, 0.26-1.29); P = 0.14). CONCLUSION: In our prospective registry, the majority of fetuses with LUTO received conservative management, which was associated with better short- and long-term outcomes. A significant proportion of these pregnancies had normal amniotic fluid volume and a gestational age at diagnosis of ≥ 24 weeks, characteristics shown to be associated with improved survival.

Novel Blood-Based Biomarkers and Disease Modifying Therapies for Alzheimer's Disease. Are We Ready for the New Era?

Recent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer's disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer's disease, of increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer's disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements.

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.

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.

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.

PROSPER: a randomised comparison of surgical treatments for rectal prolapse.

AIM: Rectal prolapse is a profoundly disabling condition, occurring mainly in elderly and parous women. There is no accepted standard surgical treatment, with previous studies limited in methodological quality and size. PROSPER aimed to address these deficiencies by comparing the relative merits of different procedures. METHOD: In a pragmatic, factorial (2 × 2) design trial, patients could be randomised between abdominal and perineal surgery (i), and suture vs resection rectopexy for those receiving an abdominal procedure (ii) or Altemeier's vs Delorme's for those receiving a perineal procedure (iii). Primary outcome measures were recurrence of the prolapse, incontinence, bowel function and quality of life scores (Vaizey, bowel thermometer and EQ-5D) measured up to 3 years. RESULTS: Two hundred and ninety-three patients were recruited: 49 were randomised between surgical approaches (i); 78 between abdominal procedures (ii); and 213 between perineal procedures (iii). Recurrence rates were higher than anticipated, but not significantly different in any comparison: Altemeier's vs Delorme's 24/102 (24%) and 31/99 (31%) [hazard ratio (HR) 0.81; 95% CI 0.47, 1.38; P = 0.4]; resection vs suture rectopexy 4/32 (13%) and 9/35 (26%) (HR 0.45; 95% CI 0.14, 1.46; P = 0.2); perineal vs abdominal 5/25 (20%) and 5/19 (26%) (HR 0.83; 95% CI 0.24, 2.86; P = 0.8). Vaizey, bowel thermometer and EQ-5D scores were not significantly different in any of the comparisons. CONCLUSION: No significant differences were seen in any of the randomised comparisons, although substantial improvements from baseline in quality of life were noted following all procedures.

Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24.

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

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.

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.

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.