Predicted leukocyte telomere length and risk of myeloid neoplasms.

Maintenance of telomere length has long been established to play a role in the biology of cancer and several studies suggest that it may be especially important in myeloid malignancies. To overcome potential bias in confounding and reverse causation of observational studies, we use both a polygenic risk score (PRS) and inverse-variance weighted (IVW) Mendelian randomization (MR) analyses to estimate the relationship between genetically predicted leukocyte telomere length (LTL) and acute myeloid leukemia (AML) risk in 498 cases and 2099 controls and myelodysplastic syndrome (MDS) risk in 610 cases and 1759 controls. Genetic instruments derived from four recent studies explaining 1.23-4.57% of telomere variability were considered. We used multivariable logistic regression to estimate odds ratios (OR, 95% confidence intervals [CI]) as the measure of association between individual single-nucleotide polymorphisms and myeloid malignancies. We observed a significant association between a PRS of longer predicted LTL and AML using three genetic instruments (OR = 4.03 per ~1200 base pair [bp] increase in LTL, 95% CI: 1.65, 9.85 using Codd et al. [Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I. et al. (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet., 45, 422-427 427e421-422.], OR = 3.48 per one-standard deviation increase in LTL, 95% CI: 1.74, 6.97 using Li et al. [Li, C., Stoma, S., Lotta, L.A., Warner, S., Albrecht, E., Allione, A., Arp, P.P., Broer, L., Buxton, J.L., Alves, A.D.S.C. et al. (2020) Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. Am. J. Hum. Genet., 106, 389-404.] and OR = 2.59 per 1000 bp increase in LTL, 95% CI: 1.03, 6.52 using Taub et al. [Taub, M.A., Conomos, M.P., Keener, R., Iyer, K.R., Weinstock, J.S., Yanek, L.R., Lane, J., Miller-Fleming, T.W., Brody, J.A., Raffield, L.M. et al. (2022) Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom., 2.] genetic instruments). MR analyses further indicated an association between LTL and AML risk (PIVW ≤ 0.049) but not MDS (all PIVW ≥ 0.076). Findings suggest variation in genes relevant to telomere function and maintenance may be important in the etiology of AML but not MDS.

Comparison of overall and patterns of care in patients with a malignant ovarian germ cell tumor by age in the United States: a National Cancer Database (2004-2016) analysis.

BACKGROUND: Women aged ≥40 years diagnosed with a malignant ovarian germ cell tumor are more likely to have poor outcomes than their younger counterparts (aged 15-39 years). OBJECTIVE: We used the National Cancer Database (NCDB) to evaluate patterns of care and overall survival for individuals diagnosed with one of the four most common histologic subtypes of malignant ovarian germ cell tumor by age group. METHODS: We identified women aged 15-90 diagnosed with ovarian germ cell tumors in the NCDB (2004-2016). Logistic regression was used to compare patterns of care, demographic, and disease characteristics by age group. Cox proportional hazards regression was used to evaluate associations between a range of demographic, clinical, and treatment characteristics with overall survival. RESULTS: A total of n=2998 patients who were diagnosed with one of the four most common histologic subtypes (immature teratoma, dysgerminoma, yolk sac tumor, and mixed germ cell) of ovarian germ cell tumor were included in the analysis. Patients aged ≥40 years diagnosed with ovarian germ cell tumors were more likely to have co-morbidities, a bilateral tumor, higher stage of disease, receive chemotherapy only, and have a residual tumor after resection as compared with patients aged <40 years. Moreover, women aged ≥40 years had the highest risk of death (reference: 15-24 year olds; HR=5.37, 95% CI 3.76 to 7.66) after adjustment for demographic characteristics, tumor histology, and treatment received. In stratified analyses, women aged ≥40 years had significantly worse overall survival at each disease stage and histologic subtype. CONCLUSION: Findings suggest that women aged ≥40 years who are diagnosed with ovarian germ cell tumors have worse overall survival than those aged <40, independent of stage, disease characteristics, and treatment. Our study highlights the need for future research to better understand reasons for poorer outcomes in women aged ≥40 years.

Comparison of phenobarbital-adjunct versus benzodiazepine-only approach for alcohol withdrawal syndrome in the ED.

OBJECTIVES: To compare a phenobarbital-adjunct versus benzodiazepine-only approach for the management of alcohol withdrawal syndrome in the emergency department (ED) with regard to the need for intensive care unit (ICU) admission, severity of symptoms on ED discharge, and complications. METHODS: This was a retrospective cohort study conducted in two academic EDs in the United States. Adult patients seen in the ED with a diagnosis of alcohol withdrawal syndrome were included. Patients were categorized into two groups based on whether phenobarbital was administered in the ED: 1) phenobarbital group (with or without benzodiazepines) or 2) non-phenobarbital group. The primary outcome measure was the need for ICU admission. Secondary outcomes included Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at ED discharge, and complications. Complications were a composite of death, need for intubation, hypotension or vasopressor use, seizures, and hospital acquired pneumonia. RESULTS: The study cohort included 209 patients (phenobarbital = 97, non-phenobarbital = 112). The mean (standard deviation) age was 49 (12) years and 85% (n = 178) were male. A similar proportion of patients in the phenobarbital (14%, n = 14) and non-phenobarbital (11%, n = 12) groups required ICU admission (p = 0.529). The median CIWA-Ar score on ED discharge was 7 (IQR 4-12) points in the phenobarbital group and 7 (IQR 4-14) points in the non-phenobarbital group (p = 0.752). The occurrence of complications was also similar in the phenobarbital (9%, n = 9) and non-phenobarbital groups (11%, n = 10). CONCLUSION: Adjunctive phenobarbital use in the ED for alcohol withdrawal syndrome did not result in decreased ICU admission, severity of symptoms, or complications.

Characteristics and knowledge synthesis approach for 456 network meta-analyses: a scoping review.

BACKGROUND: Network meta-analysis (NMA) has become a popular method to compare more than two treatments. This scoping review aimed to explore the characteristics and methodological quality of knowledge synthesis approaches underlying the NMA process. We also aimed to assess the statistical methods applied using the Analysis subdomain of the ISPOR checklist. METHODS: Comprehensive literature searches were conducted in MEDLINE, PubMed, EMBASE, and Cochrane Database of Systematic Reviews from inception until April 14, 2015. References of relevant reviews were scanned. Eligible studies compared at least four different interventions from randomised controlled trials with an appropriate NMA approach. Two reviewers independently performed study selection and data abstraction of included articles. All discrepancies between reviewers were resolved by a third reviewer. Data analysis involved quantitative (frequencies) and qualitative (content analysis) methods. Quality was evaluated using the AMSTAR tool for the conduct of knowledge synthesis and the ISPOR tool for statistical analysis. RESULTS: After screening 3538 citations and 877 full-text papers, 456 NMAs were included. These were published between 1997 and 2015, with 95% published after 2006. Most were conducted in Europe (51%) or North America (31%), and approximately one-third reported public sources of funding. Overall, 84% searched two or more electronic databases, 62% searched for grey literature, 58% performed duplicate study selection and data abstraction (independently), and 62% assessed risk of bias. Seventy-eight (17%) NMAs relied on previously conducted systematic reviews to obtain studies for inclusion in their NMA. Based on the AMSTAR tool, almost half of the NMAs incorporated quality appraisal results to formulate conclusions, 36% assessed publication bias, and 16% reported the source of funding. Based on the ISPOR tool, half of the NMAs did not report if an assessment for consistency was conducted or whether they accounted for inconsistency when present. Only 13% reported heterogeneity assumptions for the random-effects model. CONCLUSIONS: The knowledge synthesis methods and analytical process for NMAs are poorly reported and need improvement.

Synthesis and Structure-Activity Relationship Analysis of 5-HT7 Receptor Antagonists: Piperazin-1-yl Substituted Unfused Heterobiaryls.

A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT7 receptors. The goal of this project was to elucidate the structural features that affect the 5-HT7 binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl)pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT7 binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT7 binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile-compound 12 can be regarded as a dual 5-HT7/5-HT2AR ligand, and 13 as a multi-receptor (5-HT7, 5-HT2A, 5-HT6 and D2) agent.

What Guidance are Economists Given on How to Present Economic Evaluations for Policymakers? A Systematic Review.

OBJECTIVES: To systematically review health economic guidelines for information on how to present health economic evaluations and consider implications for nontechnical audiences such as policymakers. METHODS: Electronic databases and supplementary sources were searched for economic evaluation guidelines. Guidelines were critically appraised. Descriptive characteristics, standard formats, supports for nontechnical audiences, presentation approaches, and common reporting recommendations were extracted. Frequencies were tabulated and trends identified. RESULTS: Thirty-one guidelines were included. Twenty-two guidelines include a standard reporting format with some sample tables and graphs. Common presentation approaches include well-cited tables of data sources, transparent model diagrams and descriptions, disaggregated results, and tabular and graphical displays of sensitivity analyses. Despite most guidelines being funded by policymakers, only five guidelines provided advice on presenting economic evaluations to noneconomists. However, 11 guidelines included a glossary of economic terminology for nontechnical readers. Common concepts that may require further explanation include differences in economic perspectives, appropriateness of time horizons, how economic outcomes such as quality-adjusted life-years relate to their component clinical outcomes, and choice of sensitivity analyses. CONCLUSIONS: Health economists have consistent presentation formats and common reporting elements that should be considered when developing user-friendly explanations for general audiences. These overlap with policymakers' informational needs but may not be sufficient for understanding by nontechnical audiences. Developing presentation formats and tools that incorporate viewpoints of both economists and noneconomists will allow for better application of the results of economic evaluations and enhance the transparency and legitimacy of decision-making processes that are informed by economic evaluations.

Association of urinary biomarkers of tobacco exposure with lung cancer risk in African American and White cigarette smokers in the Southern Community Cohort Study.

BACKGROUND: After accounting for smoking history lung cancer incidence is greater in African Americans than Whites. In the Multiethnic Cohort, total nicotine equivalents (TNE) are higher in African Americans than Whites at similar reported cigarettes per day (CPD). Greater toxicant uptake per cigarette may contribute to the greater lung cancer risk of African Americans. METHODS: In a nested case-control lung cancer study within the Southern Community Cohort, smoking-related biomarkers were measured in 259 cases and 503 controls (40% White, 56% African American). TNE, the trans-3-hydroxycotinine:cotinine ratio, 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), mercapturic acid metabolites of volatile organic compounds, phenanthrene metabolites, cadmium, and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid (8-iso-PGF2α) were quantified in urine. Unconditional logistic regression was used to estimate the odds ratios and 95% confidence intervals for each biomarker and lung cancer risk. RESULTS: TNE, NNAL and cadmium were higher in cases than controls (adjusted for age, race, sex, body mass index (BMI) and CPD). Among cases, these levels were higher in African Americans compared to Whites. After accounting for age, sex, BMI and pack-years, a one-SD increase in log-TNE (OR=1.30; 95% CI: 1.10-1.54) and log-NNAL (OR=1.27; 95% CI: 1.03-1.58 with TNE adjustment) were associated with lung cancer risk. In this study, where NNAL concentration is relatively high, the association for log-TNE was attenuated after adjustment for log-NNAL. CONCLUSION: Smoking-related biomarkers provide additional information for lung cancer risk in smokers beyond smoking pack-years. IMPACT: Urinary NNAL, TNE and cadmium concentrations in current smokers, particularly African American smokers, may be useful for predicting lung cancer risk.

Assessing the Role of Infant and Toddler MenACWY Immunisation in the UK: Does the Adolescent MenACWY Programme Provide Sufficient Protection?

A combined Haemophilus influenzae type b (Hib)/meningococcal serogroup C (MenC) vaccine will soon be unavailable in the UK immunisation schedule due to discontinuation by the manufacturer. An interim statement by the Joint Committee on Vaccination and Immunisation (JCVI) advises stopping MenC immunisation at 12 months of age when this occurs. We undertook an analysis of the public health impact of various potential meningococcal vaccination strategies in the UK in the absence of the Hib/MenC vaccine. A static population-cohort model was developed evaluating the burden of IMD (using 2005-2015 epidemiological data) and related health outcomes (e.g., cases, cases with long-term sequelae, deaths), which allows for the comparison of any two meningococcal immunisation strategies. We compared potential strategies that included different combinations of infant and/or toddler MenACWY immunisations with the anticipated future situation in which a 12-month MenC vaccine is not used, but the MenACWY vaccine is routinely given in adolescents. The most effective strategy is combining MenACWY immunisation at 2, 4, and 12 months of age with the incumbent adolescent MenACWY immunisation programme, resulting in the prevention of an additional 269 IMD cases and 13 fatalities over the modelling period; of these cases, 87 would be associated with long-term sequelae. Among the different vaccination strategies, it was observed that those with multiple doses and earlier doses provided the greatest protection. Our study provides evidence suggesting that the removal of the MenC toddler immunisation from the UK schedule would potentially increase the risk of unnecessary IMD cases and have a detrimental public health impact if not replaced by an alternate infant and/or toddler programme. This analysis supports that infant and toddler MenACWY immunisation can provide maximal protection while complementing both infant/toddler MenB and adolescent MenACWY immunisation programmes in the UK.

Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes.

BACKGROUND: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes. RESULTS: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers. CONCLUSIONS: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696 .

Recording blood pressure readings in elderly patients' charts: what patient and physician characteristics make it more likely?

OBJECTIVE: To identify patient and physician characteristics associated with family physicians recording blood pressure (BP) measurements in the medical charts of their elderly patients. DESIGN: Retrospective review of patients' charts during a 12-month period and baseline questionnaire on the sociodemographic and practice characteristics of family physicians participating in the Community Hypertension Assessment Trial. The chart review collected data on patients' demographics, cardiovascular risk factors, antihypertensive medications, number of visits to family physicians, and number of BP readings recorded. SETTING: Non-academic family practices in Hamilton and Ottawa, Ont. PARTICIPANTS: Data were abstracted from the charts of 55 randomly selected regular elderly patients (65 years old and older) from each of 28 participating family practices (N = 1540 charts). MAIN OUTCOME MEASURE: Number of recordings of BP measurements in medical charts during a 12-month period. RESULTS: About 16% (241/1540) of elderly patients had not had their BP recorded in their charts during the 12-month review period. Among this 16%, almost half (47%, 114/241) had not had a BP measurement recorded during the previous 24 months. Multivariate analysis indicated that the likelihood of BP recording increased with the number of visits made to family physicians and was greater among patients taking antihypertensive medications or diagnosed with hypertension. Physicians who had more recently graduated from medical school (< or = 24 years) were more likely to record BP measurements. CONCLUSION: Hypertension guidelines recommend that, for patients at risk, BP be measured and recorded at each office visit. Although more than 84% of older patients had at least 1 BP reading documented in their charts, patients who were already diagnosed with hypertension or who made frequent visits to the office were more likely to have their BP measured and recorded. A more systematic approach to monitoring elderly patients who visit their family physicians less frequently or who are not currently diagnosed with hypertension is needed.

Influenza vaccination and decisional conflict among regulated and unregulated direct nursing care providers in long-term-care homes.

The purpose of this study was to determine whether direct nursing care providers have decisional conflict about receiving influenza vaccinations and characteristics associated with decisional conflict. The researchers used a self-administered questionnaire mailed to direct nursing care providers in two long-term-care organizations. Most direct nursing care providers in both organizations (80% and 93%, respectively) intended to get the influenza vaccine. Unregulated direct nursing care providers had more decisional conflict than regulated providers, especially related to feeling uninformed about the pros and cons of influenza vaccination. Unclear valuing of the pros and cons of influenza vaccination was related to the age of the direct care providers in both organizations. Decisional conflict and influenza vaccination practices may be determined, in part, by age and by the culture of a health care organization. A decision aid to improve knowledge and clarify values may improve decision quality and increase influenza vaccination rates.

Reflections on Canada's public health enterprise in the 21st century.

In their paper, "The Public Health Enterprise: Examining Our Twenty-First-Century Policy Challenges," Tilson and Berkowitz outline six challenges for the United States public health enterprise: infrastructure, essential services, preparedness, accountability and measurement, workforce and the research agenda. Canada also has challenges in these areas. This paper briefly outlines examples of what is being done to respond to these challenges, the current state of public health in Canada and directions being taken in Canada for the future. There are striking similarities in the public health system challenges facing the United States and Canada, despite major differences in organization and financing of healthcare in the two countries. Planning, implementation and evaluation of public health approaches require different management skills and knowledge than for personal healthcare. Both countries must keep up their recent momentum to improve their official public health infrastructure, agreement on essential services, emergency preparedness, accountability and measurement, workforce and research agenda.

A scoping review of pediatric economic evaluation 1980-2014: do trends over time reflect changing priorities in evaluation methods and childhood disease?

INTRODUCTION: Economic evaluations conducted in children have unique features compared to adults. Important developments in pediatric economic evaluation in recent years include new options for valuing health states for cost-utility analysis (CUA) and shifting child health priorities. The Pediatric Economic Database Evaluation (PEDE) project includes a comprehensive database of pediatric health economic evaluations published since 1980. The objective of this scoping review was to identify trends over time in the use of CUA and other analytic techniques, and the therapeutic areas chosen for study. Areas covered: Medical and grey literature were searched, key characteristics were extracted, frequencies were tabulated and cross-tabulations were performed. Differences between early (1980 and 1999) and late (2000 and 2014) periods were assessed using a chi-squared statistic. Of the 2,776 pediatric economic evaluations published between 1980 and 2014, substantially more were cost-effectiveness analyses (CEAs) and CUAs than cost benefit analyses and cost minimization analyses (63.9 and 24.9% versus 7.6 and 3.6%, respectively). This pattern was consistent regardless of the type of intervention, disease or age group studied. A trend toward higher proportions of CUAs and CEAs was evident in the later period (X2 p < 0.0001). Other significant trends included a higher proportion of studies of preventive interventions (X2 p < 0.0001), and more studies in children aged 1 to 12 years and fewer in perinates in the later period (X2 p < 0.0001). Overall the most common disease class studied was infectious diseases (29.2%). Expert commentary: Pediatric economic evaluation continues to grow in volume and methodologic complexity. While CUAs have increased, whether their quality has improved remains unknown. Although most studies are in infectious disease, the volume of publications may not align with emerging child health priorities such as adolescent health, injury, developmental disabilities, mental health, and the use of personalized medicine. Increasing economic evaluations in these areas will enhance pediatric decision-making.

Using Procalcitonin in Septic Shock to Guide Antibacterial Therapy.

Over the last decade, the biomarkers procalcitonin and C-reactive protein have gained interest in sepsis research. Procalcitonin is a unique biomarker that is specific to bacterial infection and has demonstrated utility in the risk stratification of patients with potential life-threatening bacterial infections. In addition, procalcitonin has been documented as having a role in reducing the rate of unnecessary antibiotics while positively impacting antibiotic resistance rates and cost savings. The purposes of this review article are to discuss the clinical relevance of C-reactive protein and procalcitonin as diagnostic and prognostic markers for sepsis with a focus on the use of serial procalcitonin levels as a component of antibiotic stewardship programs. The federal government has recently become invested in combating the progression of antibiotic resistance; a 5-year national plan has been developed to address these concerns. Establishing a reliable antibiotic stewardship program is one of the goals of this national plan.

What guidance are researchers given on how to present network meta-analyses to end-users such as policymakers and clinicians? A systematic review.

INTRODUCTION: Network meta-analyses (NMAs) are complex methodological approaches that may be challenging for non-technical end-users, such as policymakers and clinicians, to understand. Consideration should be given to identifying optimal approaches to presenting NMAs that help clarify analyses. It is unclear what guidance researchers currently have on how to present and tailor NMAs to different end-users. METHODS: A systematic review of NMA guidelines was conducted to identify guidance on how to present NMAs. Electronic databases and supplementary sources were searched for NMA guidelines. Presentation format details related to sample formats, target audiences, data sources, analysis methods and results were extracted and frequencies tabulated. Guideline quality was assessed following criteria developed for clinical practice guidelines. RESULTS: Seven guidelines were included. Current guidelines focus on how to conduct NMAs but provide limited guidance to researchers on how to best present analyses to different end-users. None of the guidelines provided reporting templates. Few guidelines provided advice on tailoring presentations to different end-users, such as policymakers. Available guidance on presentation formats focused on evidence networks, characteristics of individual trials, comparisons between direct and indirect estimates and assumptions of heterogeneity and/or inconsistency. Some guidelines also provided examples of figures and tables that could be used to present information. CONCLUSIONS: Limited guidance exists for researchers on how best to present NMAs in an accessible format, especially for non-technical end-users such as policymakers and clinicians. NMA guidelines may require further integration with end-users' needs, when NMAs are used to support healthcare policy and practice decisions. Developing presentation formats that enhance understanding and accessibility of NMAs could also enhance the transparency and legitimacy of decisions informed by NMAs.