Folic acid fortification and public health: Report on threshold doses above which unmetabolised folic acid appear in serum

BACKGROUND: All flour in the USA is fortified with folic acid at a level of 140 μg/100 g which is estimated to supply an extra 100 μg daily to the average diet. Some researchers have advocated that this be increased to double and even four times this amount. Based on previous research these higher levels are likely to lead to the appearance of unmetabolised vitamin in the circulation, which may have safety implications for sub-groups of the population. The UK and the Republic of Ireland will likely introduce mandatory fortification also in the next year or so. The aim of this study was to capture the short-term effect of folic acid fortification on unmetabolised folic acid in serum after chronic consumption of folic acid. METHODS: After pre-saturation with 400 μg folic acid supplements daily for 14-weeks, healthy folate replete adults (n = 20) consumed folic acid fortified bread, at three different levels (400 μg, 200 μg, 100 μg) over a period of one week each. The dose was administered in two-equal sized slices consumed at 09.00 hrs and 13.00 hrs. Serum samples for total folate and folic acid were collected at baseline, after 14-weeks of supplementation, and pre and post (at 1, 2, 3 and 4 hours) each dose tested. RESULTS: Unmetabolised folic acid was detected after the 14-week supplementation period. Folic acid was not detected in either the 200 μg or 100 μg (current US regime) doses tested but was present at the highest level (400 μg) tested. CONCLUSION: Our findings suggest that persons exposed to the current US fortification programme supplying an average of 100 μg per day or less are unlikely to have unmetabolised folic acid in serum. It also seems that daily consumption of the higher level of 200 μg or less is unlikely to be problematic. Increasing the level however to 400 μg on the other hand is likely to lead to unmetabolised folic acid appearance

Capacitated Center Problems with Two-Sided Bounds and Outliers

In recent years, the capacitated center problems have attracted a lot of research interest. Given a set of vertices $V$, we want to find a subset of vertices $S$, called centers, such that the maximum cluster radius is minimized. Moreover, each center in $S$ should satisfy some capacity constraint, which could be an upper or lower bound on the number of vertices it can serve. Capacitated $k$-center problems with one-sided bounds (upper or lower) have been well studied in previous work, and a constant factor approximation was obtained. We are the first to study the capacitated center problem with both capacity lower and upper bounds (with or without outliers). We assume each vertex has a uniform lower bound and a non-uniform upper bound. For the case of opening exactly $k$ centers, we note that a generalization of a recent LP approach can achieve constant factor approximation algorithms for our problems. Our main contribution is a simple combinatorial algorithm for the case where there is no cardinality constraint on the number of open centers. Our combinatorial algorithm is simpler and achieves better constant approximation factor compared to the LP approach

Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis

BACKGROUND: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. METHODS: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. FINDINGS: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10(-10)), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10(-36)) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. INTERPRETATION: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom

Children and older adults exhibit distinct sub-optimal cost-benefit functions when preparing to move their eyes and hands

"© 2015 Gonzalez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited"Numerous activities require an individual to respond quickly to the correct stimulus. The provision of advance information allows response priming but heightened responses can cause errors (responding too early or reacting to the wrong stimulus). Thus, a balance is required between the online cognitive mechanisms (inhibitory and anticipatory) used to prepare and execute a motor response at the appropriate time. We investigated the use of advance information in 71 participants across four different age groups: (i) children, (ii) young adults, (iii) middle-aged adults, and (iv) older adults. We implemented 'cued' and 'non-cued' conditions to assess age-related changes in saccadic and touch responses to targets in three movement conditions: (a) Eyes only; (b) Hands only; (c) Eyes and Hand. Children made less saccade errors compared to young adults, but they also exhibited longer response times in cued versus non-cued conditions. In contrast, older adults showed faster responses in cued conditions but exhibited more errors. The results indicate that young adults (18 -25 years) achieve an optimal balance between anticipation and execution. In contrast, children show benefits (few errors) and costs (slow responses) of good inhibition when preparing a motor response based on advance information; whilst older adults show the benefits and costs associated with a prospective response strategy (i.e., good anticipation)

Prostate Cancer Foundation Hormone-Sensitive Prostate Cancer Biomarker Working Group Meeting Summary.

Androgen deprivation therapy remains the backbone therapy for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). In recent years, several treatments, including docetaxel, abiraterone + prednisone, enzalutamide, and apalutamide, have each been shown to demonstrate survival benefit when used upfront along with androgen deprivation therapy. However, treatment selection for an individual patient remains a challenge. There is no high level clinical evidence for treatment selection among these choices based on biological drivers of clinical disease. In August 2020, the Prostate Cancer Foundation convened a working group to meet and discuss biomarkers for hormone-sensitive prostate cancer, the proceedings of which are summarized here. This meeting covered the state of clinical and biological evidence for systemic therapies in the mHSPC space, with emphasis on charting a course for the generation, interrogation, and clinical implementation of biomarkers for treatment selection

Lack of consensus identifies important areas for future clinical research: Advanced Prostate Cancer Consensus Conference (APCCC) 2019 findings

BACKGROUND: Innovations in treatments, imaging and molecular characterisation have improved outcomes for people with advanced prostate cancer; however, many aspects of clinical management are devoid of high-level evidence. At the Advanced Prostate Cancer Consensus Conference (APCCC) 2019, many of these topics were addressed, and consensus was not always reached. The results from clinical trials will most reliably plus the gaps. METHODS: An invited panel of 57 experts voted on 123 multiple-choice questions on clinical management at APCCC 2019. No consensus was reached on 88 (71.5%) questions defined as <75% of panellists voting for the same answer option. We reviewed clinicaltrials.gov to identify relevant ongoing phase III trials in these areas of non-consensus. RESULTS: A number of ongoing phase III trials were identified that are relevant to these non-consensus issues. However, many non-consensus issues appear not to be addressed by current clinical trials. Of note, no phase III but only phase II trials were identified, investigating side effects of hormonal treatments and their management. CONCLUSIONS: Lack of consensus almost invariably indicates gaps in existing evidence. The high percentage of questions lacking consensus at APCCC 2019 highlights the complexity of advanced prostate cancer care and the need for robust, clinically relevant trials that can fill current gaps with high-level evidence. Our review of these areas of non-consensus and ongoing trials provides a useful summary, indicating areas in which future consensus may soon be reached. This review may facilitate academic investigators to identify and prioritise topics for future research

Integrating economic and health evidence to inform Covid-19 policy in low- and middle- income countries

This is the final version. Available on open access from F1000 Research via the DOI in this recordData availability: No data are associated with this article.Covid-19 requires policy makers to consider evidence on both population health and economic welfare. Over the last two decades, the field of health economics has developed a range of analytical approaches and contributed to the institutionalisation of processes to employ economic evidence in health policy. We present a discussion outlining how these approaches and processes need to be applied more widely to inform Covid-19 policy; highlighting where they may need to be adapted conceptually and methodologically, and providing examples of work to date. We focus on the evidential and policy needs of low- and middle-income countries; where there is an urgent need for evidence to navigate the policy trade-offs between health and economic well-being posed by the Covid-19 pandemic.Wellcome Trus

Event-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation

PURPOSE: Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion. METHODS: EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R2 ≥ 0.7. RESULTS: Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the R2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS. CONCLUSION: EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials

Optimal constraint-based decision tree induction from itemset lattices

International audienceIn this article we show that there is a strong connection between decision tree learning and local pattern mining. This connection allows us to solve the computationally hard problem of finding optimal decision trees in a wide range of applications by post-processing a set of patterns: we use local patterns to construct a global model. We exploit the connection between constraints in pattern mining and constraints in decision tree induction to develop a framework for categorizing decision tree mining constraints. This framework allows us to determine which model constraints can be pushed deeply into the pattern mining process, and allows us to improve the state-of-the-art of optimal decision tree induction