Partial Nitritation/Anammox and biological phosphorus removal integration in a single bioreactor under mainstream conditions.

Anammox-based nitrogen removal and enhanced biological phosphorus removal (EBPR) are increasingly applied for nutrient removal from wastewater, but are typically operated in separate reactors. Here, a novel process for integrated partial nitritation/anammox (PN/A) and EBPR in a single reactor employing integrated fixed film activated sludge was tested. The reactor was fed with mainstream municipal wastewater (5.4 ± 1.3 g COD/g N) at 20 °C for 243 days. Robust ammonium, total inorganic nitrogen, and orthophosphate removal efficiencies of 94 ± 4 %, 87 ± 7 % and 92 ± 7 % were achieved. Nitrite-oxidizing organisms suppression and ammonia-oxidizing organisms retention were achieved via solids retention time control, intermittent aeration, and suspended versus attached biomass population segregation. The contribution of anammox to nitrogen removal increased from 24 % to 74 %. In parallel, a substantial enrichment of Tetrasphaera polyphosphate accumulating organisms was observed. This work demonstrates a novel intensified bioprocess coupling PN/A and EBPR in the same reactor for efficient nutrient removal from wastewater.

Impact of operational strategies on a sidestream enhanced biological phosphorus removal (S2EBPR) reactor in a carbon limited wastewater plant.

Water resource recovery facilities are faced with stringent effluent phosphorus limits to reduce nutrient pollution. Enhanced biological phosphorus removal (EBPR) is the most common biological route to remove phosphorus; however, many facilities struggle to achieve consistent performance due to limited carbon availability in the influent wastewater. A promising process to improve carbon availability is through return activated sludge (RAS) fermentation via sidestream EBPR (S2EBPR). In this study, a full-scale S2EBPR pilot was operated with a sidestream plus carbon configuration (SSRC) at a carbon-limited facility. A model based on the pilot test was developed and calibrated in the SUMO platform and used to explore routes for improving orthophosphate (OP) effluent compliance. Modeling results showed that RAS diversion by itself was not sufficient to drive OP removal to permit limits of 1 mg L-1, therefore, other strategies were evaluated. Supplemental carbon addition of MicroC® at 1.90 L min-1 and controlling the phosphorus concentration below 3.5 mgP L-1 in the primary effluent (PE) proved to be valid supplemental strategies to achieve OP removal below 1 mg L-1 most of the time. In particular, the proposed supplemental carbon flow rate would result in an improvement of the rbCOD:P ratio from 17:1 to 26:1. The synergistic approach of RAS diversion and supplemental carbon addition increased the polyphosphate accumulating organisms (PAO) population while minimizing the supplemental carbon needed to achieve consistent phosphorus removal. Overall, this pilot and modeling study shows that joint strategies, including RAS diversion, carbon addition and PE control, can be effective to achieve optimal control of OP effluent.

Assessment of the quality and content of clinical practice guidelines (CPGs) for vitamin D and for immigrants using the AGREE-II instrument: a protocol for systematic review.

INTRODUCTION: Worldwide, more immigrants experience vitamin D (vitD) deficiency than non-immigrants, which is attributed to ethnic variations, place or region of birth, skin pigmentation, clothing style, and resettlement-related changes in diet, physical activity, and sun exposure. Current recommendations in clinical practice guidelines (CPGs) concerning vitD are inadequate to address vitD deficiency among immigrants. CPGs may also lack guidance for physicians on vitD supplementation for immigrants. Moreover, there are concerns about the overall quality of these CPGs. OBJECTIVES: This systematic review will collate and critically appraise CPGs relevant to immigrants' health and vitD. Moreover, we will evaluate whether the CPGs of vitD including recommendations for immigrants and clarify whether the CPGs of immigrants include recommendations on vitD. METHODS: A systematic search of Ovid MEDLINE® ALL, EMBASE, and Turning Research Into Practice (TRIP) electronic databases, guideline repositories, and gray literature will be conducted to identify relevant CPGs. Two reviewers will independently evaluate the methodological quality of the retrieved guidelines using the Appraisal of Guidelines, Research, and Evaluation-II (AGREE-II) instrument. CPGs scoring ≥60% in at least four domains, including "rigor of development," will be considered high quality. CONCLUSION: Evaluating the quality and content of relevant CPGs may support researchers in developing national and global guidelines for immigrants. Furthermore, it may support vitD testing, nutritional counseling, and supplementation for vulnerable immigrant sub-populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021240562.

Personalized medicine in rheumatoid arthritis: Combining biomarkers and patient preferences to guide therapeutic decisions.

The last few decades have seen major therapeutic advancements in rheumatoid arthritis (RA) therapeutics. New disease-modifying antirheumatic drugs (DMARDs) have continued to emerge, creating more choices for people. However, no therapeutic works for all patients. Each has its own inherent benefits, risks, costs, dosing, and monitoring considerations. In parallel, there has been a focus on personalized medicine initiatives that tailor therapeutic decisions to patients based on their unique characteristics or biomarkers. Personalized effect estimates require an understanding of a patient's baseline probability of response to treatment and data on the comparative effectiveness of the available treatments. However, even if accurate risk prediction models are available, trade-offs often still need to be made between treatments. In this paper, we review the history of RA therapeutics and progress that has been made toward personalized risk predictive models for DMARDs, outlining where knowledge gaps still exist. We further review why patient preferences play a key role in a holistic view of personalized medicine and how this links with shared decision-making. We argue that a "preference misdiagnosis" may be equally important as a medical misdiagnosis but is often overlooked.

Insights into Nitrous Oxide Mitigation Strategies in Wastewater Treatment and Challenges for Wider Implementation.

Nitrous oxide (N2O) emissions account for the majority of the carbon footprint of wastewater treatment plants (WWTPs). Many N2O mitigation strategies have since been developed while a holistic view is still missing. This article reviews the state-of-the-art of N2O mitigation studies in wastewater treatment. Through analyzing existing studies, this article presents the essential knowledge to guide N2O mitigations, and the logics behind mitigation strategies. In practice, mitigations are mainly carried out by aeration control, feed scheme optimization, and process optimization. Despite increasingly more studies, real implementation remains rare, which is a combined result of unclear climate change policies/incentives, as well as technical challenges. Five critical technical challenges, as well as opportunities, of N2O mitigations were identified. It is proposed that (i) quantification methods for overall N2O emissions and pathway contributions need improvement; (ii) a reliable while straightforward mathematical model is required to quantify benefits and compare mitigation strategies; (iii) tailored risk assessment needs to be conducted for WWTPs, in which more long-term full-scale trials of N2O mitigation are urgently needed to enable robust assessments of the resulting operational costs and impact on nutrient removal performance; (iv) current mitigation strategies focus on centralized WWTPs, more investigations are warranted for decentralised systems, especially decentralized activated sludge WWTPs; and (v) N2O may be mitigated by adopting novel strategies promoting N2O reduction denitrification or microorganisms that emit less N2O. Overall, we conclude N2O mitigation research is reaching a maturity while challenges still exist for a wider implementation, especially in relation to the reliability of N2O mitigation strategies and potential risks to nutrient removal performances of WWTPs.

Integrated omics analyses reveal differential gene expression and potential for cooperation between denitrifying polyphosphate and glycogen accumulating organisms.

Unusually high accumulation of the potent greenhouse gas nitrous oxide (N2 O) has previously been documented in denitrifying biological phosphorus (P) removal bioprocesses, but the roles of differential denitrification gene expression patterns and ecological interactions between key functional groups in driving these emissions are not well understood. To address these knowledge gaps, we applied genome-resolved metagenomics and metatranscriptomics to a denitrifying bioprocess enriched in as-yet-uncultivated denitrifying polyphosphate accumulating organisms (PAOs) affiliated with Candidatus Accumulibacter. The six transcriptionally most active populations in the community included three co-occurring Accumulibacter strains affiliated with clades IF (a novel clade identified in this study), IA and IC, a competing glycogen accumulating organism (GAO) affiliated with Competibacteraceae (GAO1), a Gammaproteobacteria PR6 and an Anaerolineae CH7. Strongly elevated expression of nitrite reductase genes compared to nitrous oxide reductase genes was observed in the overall community and in Accumulibacter populations, suggesting a strong role for differential gene expression in driving N2 O accumulation. Surprisingly, while ~90% of the nirS gene transcripts were expressed by the three co-occurring PAO populations, ~93% of the norB gene transcripts were expressed by GAO1 and ~75% of the norZ gene transcripts were mapped to PR6 and several other non-PAO flanking populations. This suggests the potential for cooperation between flanking populations and PAOs in reducing denitrification intermediates. Such cooperation may benefit the community by reducing the accumulation of toxic nitric oxide.

Dietary Reference Intakes based on chronic disease endpoints: outcomes from a case study workshop for omega 3's EPA and DHA.

Given the focus on developing Dietary Reference Intakes (DRIs) based on chronic disease risk reduction and recent research for omega-3 long chain PUFA since the last DRI review, the Canadian Nutrition Society convened a panel of stakeholders for a 1-day workshop in late 2019. Attendees discussed the new NASEM guidelines for establishing DRI values based on chronic disease risk endpoints and the strength of current evidence for EPA and DHA as it relates to the new guidelines. Novelty: Summarizes evidence and expert opinions regarding the potential for reviewing DRI values for EPA and DHA and cardiovascular disease risk and early development.

Pushing the limits of solids retention time for enhanced biological phosphorus removal: process characteristics and Accumulibacter population structure.

Reducing the solids retention time (SRT) of the enhanced biological phosphorus removal (EBPR) process can increase organic carbon diversion to the sidestream for energy recovery, thereby realizing some of the benefits of the high rate activated sludge (HRAS) process. Determining the washout (i.e. minimum) SRT of polyphosphate accumulating organisms (PAOs), therefore, allows for simultaneous phosphorus and carbon diversion for energy recovery from EBPR systems. However, few studies have investigated the washout SRT of PAOs in real wastewater, and little is known of the diversity of PAOs in high rate EBPR systems. Here we demonstrate efficient phosphorus removal (83% orthophosphate removal) in a high rate EBPR sequencing batch reactor fed real primary effluent and operated at 20 °C. Stable operation was achieved at a total SRT of 1.8 ± 0.2 days and hydraulic retention time of 3.7-4.8 hours. 16S rRNA gene sequencing data demonstrated that Accumulibacter were the dominant PAO throughout the study, with a washout aerobic SRT between 0.8 and 1.4 days. qPCR targeting the polyphosphate kinase gene revealed that Accumulibacter clades IIA, IIB and IID dominated the PAO community at low SRT operation, while clade IA was washed out at the lowest SRT values.

Catheter Ablation of Low-Voltage Areas for Persistent Atrial Fibrillation: Procedural Outcomes Using High-Density Voltage Mapping.

BACKGROUND: Several approaches have been proposed to address the challenge of catheter ablation of persistent atrial fibrillation (AF). However, the optimal ablation strategy is unknown. We sought to evaluate the efficacy of pulmonary vein isolation (PVI) plus low-voltage area (LVA) ablation using contemporary high-density mapping to identify LVA in patients with persistent AF. METHODS: Consecutive patients accepted for AF catheter ablation were studied. High-density bipolar voltage mapping data were acquired in sinus rhythm using multipolar catheters to detect LVA (defined as bipolar voltage < 0.5 mV). Semiautomated impedance-based software was used to ensure catheter contact during data collection. Patients underwent PVI + LVA ablation (if LVA present). RESULTS: A total of 145 patients were studied; 95 patients undergoing PVI + LVA ablation were compared with 50 controls treated with PVI only. Average age was 61 ± 10 years, and 80% were male. Baseline characteristics were comparable. Freedom from atrial tachycardia/AF at 18 months was 72% after PVI + LVA ablation vs 58% in controls (P = 0.022). Median procedure duration (273 [240, 342] vs 305 [262, 360] minutes; P = 0.019) and radiofrequency delivery (50 [43, 63] vs 55 [35, 68] minutes; P = 0.39) were longer in the PVI + LVA ablation group. Multivariable analysis showed that the ablation strategy (PVI + LVA) was the only independent predictor of freedom from atrial tachycardia/AF (hazard ratio, 0.53; 95% confidence interval, 0.29-0.96; P = 0.036). There were no adverse safety outcomes associated with LVA ablation. CONCLUSIONS: An individualized strategy of high-density mapping to assess the atrial substrate followed by PVI combined with LVA ablation is associated with improved outcomes. Adequately powered randomized clinical trials are needed to determine the role of PVI + LVA ablation for persistent AF.

Assessing the effect of interventions for axial spondyloarthritis according to the endorsed ASAS/OMERACT core outcome set: a meta-research study of trials included in Cochrane reviews.

The Assessment of SpondyloArthritis international Society (ASAS) has defined core sets for (i) symptom-modifying anti-rheumatic drugs (SM-ARD), (ii) clinical record keeping, and (iii) disease-controlling anti-rheumatic therapy (DC-ART). These include the following domains for all three core sets: "physical function," "pain," "spinal mobility," "spinal stiffness," and "patient's global assessment" (PGA). The core set for clinical record keeping further includes the domains "peripheral joints/entheses" and "acute phase reactants," and the core set for DC-ART further includes the domains "fatigue" and "spine radiographs/hip radiographs." The Outcome Measures in Rheumatology (OMERACT) endorsed the core sets in 1998.Using empirical evidence from axSpA trials, we investigated the efficacy (i.e., net benefit) according to the ASAS/OMERACT core outcome set for axSpA across all interventions tested in trials included in subsequent Cochrane reviews. For all continuous scales, we combined data using the standardized mean difference (SMD) to meta-analyze outcomes involving the same domains. Also, through meta-regression analysis, we examined the effect of the separate SMD measures (independent variables) on the primary endpoint (log [OR], dependent variable) across all trials.Based on 11 eligible Cochrane reviews, from these, 85 articles were screened; we included 43 trials with 63 randomized comparisons. Mean (SD) number of ASAS/OMERACT core outcome domains measured for SM-ARD/physical therapy trials was 4.2 (1.7). Six trials assessed all proposed domains. Mean (SD) for number of core outcome domains for DC-ART trials was 5.8 (1.7). No trials assessed all nine domains. Eight trials (16%) were judged to have inadequate (i.e., high risk of) selective outcome reporting bias. The most responsible core domains for achieving success in meeting the primary objective per trial were pain, OR (95% CI) 5.19 (2.28, 11.77), and PGA, OR (95% CI) 1.87 (1.14, 3.07). In conclusion, selective outcome reporting (and "missing data") should be reduced by encouraging the use of the endorsed ASAS/OMERACT outcome domains in clinical trials. Overall outcome reporting was good for SM-ARD/physical therapy trials and poor for DC-ART trials. Our findings suggest that both PGA and pain provide a valuable holistic construct for the assessment of improvement beyond more objective measures of spinal inflammation.

Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.

INTRODUCTION: The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. METHODS: In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. RESULTS: Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. CONCLUSIONS: Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.

Neurologists' perspectives on medical cannabis for pediatric drug-resistant epilepsy in Canada: A qualitative interview study.

PURPOSE: To understand the experiences with and perspectives of neurologists about the use of medical cannabis in the treatment of pediatric drug-resistant epilepsy. METHODS: In this qualitative study, we interviewed neurologists who provide care to children with drug-resistant epilepsy in Canada. Through semi-structured telephone interviews, we sought participants' views about and experiences with medical cannabis for the treatment of drug-resistant epilepsy in children. Here we present a thematic summary of the interviews. RESULTS: The 12 interviewed neurologists generally perceived medical cannabis as a viable treatment option for children with drug-resistant epilepsy; however, participants identified important gaps in the evidence and implications for their practices. Six themes were generated from the content of the interviews: learning about medical cannabis; perceptions about medical cannabis; discussing medical cannabis with parents; experiences with medical cannabis authorization; barriers to authorizing medical cannabis; and the impact of medical cannabis on clinical care. Of note, while some neurologists took on all aspects of the children's care, including medical cannabis, others referred interested families to non-neurology health care professionals. CONCLUSION: Our findings highlight the diverse opinions and experiences of neurologists in Canada with medical cannabis for the treatment of drug-resistant epilepsy in children, including with the authorization process and caring for children using medical cannabis. Additional education about medical cannabis may be warranted, in order to better prepare neurologists to have informed and open conversations with parents about this treatment option and to provide care for children using medical cannabis.

Cannabis-based products for pediatric epilepsy: An updated systematic review.

PURPOSE: To provide an up-to-date summary of the benefits and harms of cannabis-based products for epilepsy in children. METHODS: We updated our earlier systematic review, by searching for studies published up to May 2019. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) involving cannabis-based products administered to children with epilepsy. Outcomes were seizure freedom, seizure frequency, quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and emergency room visits. RESULTS: Thirty-five studies, including four RCTs, have assessed the benefits and harms of cannabis-based products in pediatric epilepsy (12 since April 2018). All involved cannabis-based products as adjunctive treatment, and most involved cannabidiol. In the RCTs, there was no statistically significant difference between cannabidiol and placebo for seizure freedom (relative risk 6.77, 95 % confidence interval [CI] 0.36-128.38), quality of life (mean difference [MD] 0.6, 95 %CI -2.6 to 3.9), or sleep disruption (MD -0.3, 95 %CI -0.8 to 0.2). Data from both RCTs and NRS suggest that cannabidiol reduces seizure frequency and increases treatment response; however, there is an increased risk of gastrointestinal adverse events. CONCLUSION: Newly available evidence supports earlier findings that cannabidiol probably reduces the frequency of seizures among children with drug-resistant epilepsy. PROSPERO: CRD42018084755.

Tai Chi for rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, autoimmune disease that results in joint deformity and immobility of the musculoskeletal system. The major goals of treatment are to relieve pain, reduce inflammation, slow down or stop joint damage, prevent disability, and preserve or improve the person's sense of well-being and ability to function. Tai Chi, interchangeably known as Tai Chi Chuan, is an ancient Chinese health-promoting martial art form that has been recognized in China as an effective arthritis therapy for centuries. This is an update of a review published in 2004. OBJECTIVES: To assess the benefits and harms of Tai Chi as a treatment for people with rheumatoid arthritis (RA). SEARCH METHODS: We updated the search of CENTRAL, MEDLINE, Embase, and clinical trial registries from 2002 to September 2018. SELECTION CRITERIA: We selected randomized controlled trials and controlled clinical trials examining the benefits (ACR improvement criteria or pain, disease progression, function, and radiographic progression), and harms (adverse events and withdrawals) of exercise programs with Tai Chi instruction or incorporating principles of Tai Chi philosophy. We included studies of any duration that included control groups who received either no therapy or alternate therapy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Adding three studies (156 additional participants) to the original review, this update contains a total of seven trials with 345 participants. Participants were mostly women with RA, ranging in age from 16 to 80 years, who were treated in outpatient settings in China, South Korea, and the USA. The majority of the trials were at high risk of bias for performance and detection bias, due to the lack of blinding of participants or assessors. Almost 75% of the studies did not report random sequence generation, and we judged the risk of bias as unclear for allocation concealment in the majority of studies. The duration of the Tai Chi programs ranged from 8 to 12 weeks.It is uncertain whether Tai Chi-based exercise programs provide a clinically important improvement in pain among Tai Chi participants compared to no therapy or alternate therapy. The change in mean pain in control groups, measured on visual analog scale (VAS 0 to 10 score, reduced score means less pain) ranged from a decrease of 0.51 to an increase of 1.6 at 12 weeks; in the Tai Chi groups, pain was reduced by a mean difference (MD) of -2.15 (95% confidence interval (CI) -3.19 to -1.11); 22% absolute improvement (95% CI, 11% to 32% improvement); 2 studies, 81 participants; very low-quality evidence, downgraded for imprecision, blinding and attrition bias.There was very low-quality evidence, downgraded for, blinding, and attrition, that was inconclusive for an important difference in disease activity, measured using Disease Activity Scale (DAS-28-ESR) scores (0 to 10 scale, lower score means less disease activity), with no change in the control group and 0.40 reduction (95% CI -1.10 to 0.30) with Tai Chi; 4% absolute improvement (95% CI 11% improvement to 3% worsening); 1 study, 43 participants.For the assessment of function, the change in mean Health Assessment Questionnaire (HAQ; 0 to 3 scale, lower score means better function) ranged from 0 to 0.1 in the control group, and reduced by MD 0.33 in the Tai Chi group (95% CI -0.79 to 0.12); 11% absolute improvement (95% CI 26% improvement to 4% worsening); 2 studies, 63 participants; very low-quality evidence, downgraded for imprecision, blinding, and attrition. We are unsure of an important improvement, as the results were inconclusive.Participants in Tai Chi programs were less likely than those in a control group to withdraw from studies at 8 to 12 weeks (19/180 in intervention groups versus 49/165 in control groups; risk ratio (RR) 0.40 (95% CI 0.19 to 0.86); absolute difference 17% fewer (95% CI 30% fewer to 3% fewer); 7 studies, 289 participants; low-quality evidence, downgraded for imprecision and blinding.There were no data available for radiographic progression. Short-term adverse events were not reported by group, but in two studies there was some narrative description of joint and muscle soreness and cramps; long-term adverse events were not reported. AUTHORS' CONCLUSIONS: It is uncertain whether Tai Chi has any effect on clinical outcomes (joint pain, activity limitation, function) in RA, and important effects cannot be confirmed or excluded, since all outcomes had very low-quality evidence. Withdrawals from study were greater in the control groups than the Tai Chi groups, based on low-quality evidence. Although the incidence of adverse events is likely to be low with Tai Chi, we are uncertain, as studies failed to explicitly report such events. Few minor adverse events (joint and muscle soreness and cramps) were described qualitatively in the narrative of two of the studies. This updated review provides minimal change in the conclusions from the previous review, i.e. a pain outcome.

Cost-effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic review of economic evaluations.

BACKGROUND: Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem. METHODS: We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation. DISCUSSION: Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no.: CRD42018099591 .

Genome-centric metagenomics resolves microbial diversity and prevalent truncated denitrification pathways in a denitrifying PAO-enriched bioprocess.

Denitrification is the stepwise microbial reduction of nitrate or nitrite (NO2-) to nitrogen gas via the obligate intermediates nitric oxide (NO) and nitrous oxide (N2O). Substantial N2O accumulation has been reported in denitrifying enhanced biological phosphorus removal (EBPR) bioreactors enriched in denitrifying polyphosphate accumulating organisms (DPAOs), but little is known about underlying mechanisms for N2O generation, prevalence of complete versus truncated denitrification pathways, or the impact of NO2- feed on DPAO-enriched consortia. To address this knowledge gap, we employed genome-resolved metagenomics to investigate nitrogen transformation potential in a NO2- fed denitrifying EBPR bioreactor enriched in Candidatus Accumulibacter and prone to N2O accumulation. Our analysis yielded 41 near-complete metagenome-assembled genomes (MAGs), including two co-occurring Accumulibacter strains affiliated with clades IA and IC (the first published genome from this clade) and 39 non-PAO flanking bacterial genomes. The dominant Accumulibacter clade IA encoded genes for complete denitrification, while the lower abundance Accumulibacter clade IC harbored all denitrification genes except for a canonical respiratory NO reductase. Analysis of the 39 non-PAO MAGs revealed a high prevalence of taxa harboring an incomplete denitrification pathway. Of the 27 MAGs harboring capacity for at least one step in the denitrification pathway, 10 were putative N2O producers lacking N2O reductase, 16 were putative N2O reducers that lacked at least one upstream denitrification gene, and only one harbored a complete denitrification pathway. We also documented increasing abundance over the course of reactor operation of putative N2O producers. Our results suggest that the unusually high levels of N2O production observed in this Accumulibacter-enriched consortium are linked in part to the selection for non-PAO flanking microorganisms with truncated denitrification pathways.

Cannabis-based products for pediatric epilepsy: A systematic review.

OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.

OBJECTIVE: To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. DESIGN: Randomised, phase III, double blinded international, multicentre clinical trial. SETTING: 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). PARTICIPANTS: 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. INTERVENTION: Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. MAIN OUTCOME MEASURE: The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). RESULTS: Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. CONCLUSION: Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Characterization of Low-Voltage Areas in Patients With Atrial Fibrillation: Insights From High-Density Intracardiac Mapping.

BACKGROUND: There is limited data on the scar burden in patients with atrial fibrillation (AF). In this study, we sought to evaluate the presence and extent of an abnormal left atrial (LA) substrate in patients with paroxysmal or persistent AF. METHODS: Consecutive patients who underwent initial AF catheter ablation were prospectively enrolled. Endocardial voltage mapping was acquired in sinus rhythm using multipolar mapping catheters. Automated software was used to ensure homogeneous data collection. Assessment of low-voltage area (LVA) was performed by a reviewer blinded to clinical details. RESULTS: One hundred and four patients were prospectively enrolled; 69 had paroxysmal and 35 persistent AF. The mean LA volume was 159 ± 48 mL, and the average number of LA points collected was 1308 ± 1065. Atrial LVAs were present in 23 of 69 (33%) subjects with paroxysmal and 20 of 35 (57%) with persistent AF (P = 0.02). Amongst 43 of 104 patients with scar, the average extent of LVA was 19.4 ± 21.6 cm2 and the mean percentage area was 7.6 ± 8.8%. Univariate analysis showed that age, LA volume, and persistent AF were associated with the presence of LVA. Multivariable analysis showed that age (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.00-1.11; P = 0.046) and LA volume (OR 1.02; 95% CI 1.01-1.04; P < 0.001) remained predictors of LVA. AF classification (persistent vs paroxysmal) was not a predictor of an abnormal atrial substrate (OR 1.34; 95% CI 0.4-3.9; P = 0.56). CONCLUSIONS: There is wide variability in the presence and extent of LVA in patients with paroxysmal or persistent AF. Age and LA volume were predictors of LVA. There was no correlation between AF classification and the presence of LVA.

Calcium channel blockers for primary and secondary Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. Primary Raynaud's phenomenon is not associated with underlying disease, but secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. Calcium channel blockers promote vasodilation and are commonly used when drug treatment for Raynaud's phenomenon is required. OBJECTIVES: To assess the benefits and harms of calcium channel blockers (CCBs) versus placebo for treatment of individuals with Raynaud's phenomenon with respect to Raynaud's type (primary vs secondary) and type and dose of CCBs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (May 19, 2017), MEDLINE (1946 to May 19, 2017), Embase (1947 to May 19, 2017), clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Portal. We applied no language restrictions. We also searched bibliographies of retrieved articles and contacted key experts for additional and unpublished data. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing calcium channel blockers versus placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and risk of bias and extracted trial data. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: This review contains 38 RCTs (33 cross-over RCTs) with an average duration of 7.4 weeks and 982 participants; however, not all trials reported all outcomes of interest. Nine of the identified trials studied patients with primary Raynaud's phenomenon (N = 365), five studied patients with secondary Raynaud's phenomenon (N = 63), and the rest examined a mixture of patients with primary and secondary Raynaud's phenomenon (N = 554). The most frequently encountered risk of bias types were incomplete outcome data and poor reporting of randomization and allocation methods.When researchers considered both primary and secondary Raynaud's phenomenon, evidence of moderate quality (downgraded for inconsistency) from 23 trials with 528 participants indicates that calcium channel blockers (CCBs) were superior to placebo in reducing the frequency of attacks. CCBs reduced the average number of attacks per week by six ( weighted mean difference (WMD) -6.13, 95% confidence interval (CI) -6.60 to - 5.67; I² = 98%) compared with 13.7 attacks per week with placebo. When review authors excluded Kahan 1985C, a trial showing a very large reduction in the frequency of attacks, data showed that CCBs reduced attack frequency by 2.93 per week (95% CI -3.44 to -2.43; I² = 77%).Low-quality evidence (downgraded for imprecision and inconsistency) from six trials with 69 participants suggests that the average duration of attacks did not differ in a statistically significant or clinically meaningful way between CCBs and placebo (WMD -1.67 minutes, 95% CI -3.29 to 0); this is equivalent to a -9% difference (95% CI -18% to 0%).Moderate-quality evidence (downgraded for inconsistency) based on 16 trials and 415 participants showed that CCBs reduced attack severity by 0.62 cm (95% CI -0.72 to - 0.51) on a 10-cm visual analogue scale (lower scores indicate less severity); this was equivalent to absolute and relative percent reductions of 6% (95% CI -11% to -8%) and 9% (95% CI -11% to -8%), respectively, which may not be clinically meaningful.Improvement in Raynaud's pain (low-quality evidence; downgraded for imprecision and inconsistency) and in disability as measured by a patient global assessment (moderate-quality evidence; downgraded for imprecision) favored CCBs (pain: WMD -1.47 cm, 95% CI -2.21 to -0.74; patient global: WMD -0.37 cm, 95% CI -0.73 to 0, when assessed on a 0 to 10 cm visual analogue scale, with lower scores indicating less pain and less disability). However, these effect estimates were likely underpowered, as they were based on limited numbers of participants, respectively, 62 and 92. For pain assessment, absolute and relative percent improvements were 15% (95% -22% to -7%) and 47% (95% CI -71% to -24%), respectively. For patient global assessment, absolute and relative percent improvements were 4% (95% CI -7% to 0%) and 9% (95% CI -19% to 0%), respectively.Subgroup analyses by Raynaud's type, CCB class, and CCB dose suggest that dihydropyridine CCBs in higher doses may be more effective for primary Raynaud's than for secondary Raynaud's, and CCBs likely have a greater effect in primary than in secondary Raynaud's. However, differences were small and were not found for all outcomes. Dihydropyridine CCBs were studied as they are the subgroup of CCBs that are not cardioselective and are traditionally used in RP treatment whereas other CCBs such as verapamil are not routinely used and diltiazem is not used as first line subtype of CCBs. Most trial data pertained to nifedipine.Withdrawals from studies due to adverse effects were inconclusive owing to a wide CI (risk ratio [RR] 1.30, 95% CI 0.51 to 3.33) from two parallel studies with 63 participants (low-quality evidence downgraded owing to imprecision and a high attrition rate); absolute and relative percent differences in withdrawals were 6% (95% CI -14% to 26%) and 30% (95% CI -49% to 233%), respectively. In cross-over trials, although a meta-analysis was not performed, withdrawals were more common with CCBs than with placebo. The most common side effects were headache, dizziness, nausea, palpitations, and ankle edema. However, in all trials, no serious adverse events (death or hospitalization) were reported. AUTHORS' CONCLUSIONS: Randomized controlled trials with evidence of low to moderate quality showed that CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. Higher doses may be more effective than lower doses and these CCBs may be more effective in primary RP. Although there were more withdrawals due to adverse events in the treatment groups, no serious adverse events were reported.