Visualizing External Validity: Graphical Displays to Inform the Extension of Treatment Effects from Trials to Clinical Practice.

BACKGROUND: In the presence of effect measure modification, estimates of treatment effects from randomized controlled trials may not be valid in clinical practice settings. The development and application of quantitative approaches for extending treatment effects from trials to clinical practice settings is an active area of research. METHODS: In this article, we provide researchers with a practical roadmap and four visualizations to assist in variable selection for models to extend treatment effects observed in trials to clinical practice settings and to assess model specification and performance. We apply this roadmap and visualizations to an example extending the effects of adjuvant chemotherapy (5-fluorouracil vs. plus oxaliplatin) for colon cancer from a trial population to a population of individuals treated in community oncology practices in the United States. RESULTS: The first visualization screens for potential effect measure modifiers to include in models extending trial treatment effects to clinical practice populations. The second visualization displays a measure of covariate overlap between the clinical practice populations and the trial population. The third and fourth visualizations highlight considerations for model specification and influential observations. The conceptual roadmap describes how the output from the visualizations helps interrogate the assumptions required to extend treatment effects from trials to target populations. CONCLUSIONS: The roadmap and visualizations can inform practical decisions required for quantitatively extending treatment effects from trials to clinical practice settings.

The global and regional costs of healthy and sustainable dietary patterns: a modelling study.

BACKGROUND: Adoption of healthy and sustainable diets could be essential for safe-guarding the Earth's natural resources and reducing diet-related mortality, but their adoption could be hampered if such diets proved to be more expensive and unaffordable for some populations. Therefore, we aimed to estimate the costs of healthy and sustainable diets around the world. METHODS: In this modelling study, we used regionally comparable food prices from the International Comparison Program for 150 countries. We paired those prices with estimates of food demand for different dietary patterns that, in modelling studies, have been associated with reductions in premature mortality and environmental resource demand, including nutritionally balanced flexitarian, pescatarian, vegetarian, and vegan diets. We used estimates of food waste and projections of food demand and prices to specify food system and socioeconomic change scenarios up to 2050. In the full cost accounting, we estimated diet-related health-care costs by pairing a comparative risk assessment of dietary risks with cost-of-illness estimates, and we estimated climate change costs by pairing the diet scenarios with greenhouse gas emission footprints and estimates of the social cost of carbon. FINDINGS: Compared with the cost of current diets, the healthy and sustainable dietary patterns were, depending on the pattern, up to 22-34% lower in cost in upper-middle-income to high-income countries on average (when considering statistical means), but at least 18-29% more expensive in lower-middle-income to low-income countries. Reductions in food waste, a favourable socioeconomic development scenario, and a fuller cost accounting that included the diet-related costs of climate change and health care in the cost of diets increased the affordability of the dietary patterns in our future projections. When these measures were combined, the healthy and sustainable dietary patterns were up to 25-29% lower in cost in low-income to lower-middle-income countries, and up to 37% lower in cost on average, for the year 2050. Variants of vegetarian and vegan dietary patterns were generally most affordable, and pescatarian diets were least affordable. INTERPRETATION: In high-income and upper-middle-income countries, dietary change interventions that incentivise adoption of healthy and sustainable diets can help consumers in those countries reduce costs while, at the same time, contribute to fulfilling national climate change commitments and reduce public health spending. In low-income and lower-middle-income countries, healthy and sustainable diets are substantially less costly than western diets and can also be cost-competitive in the medium-to-long term, subject to beneficial socioeconomic development and reductions in food waste. A fuller accounting of the costs of diets would make healthy and sustainable diets the least costly option in most countries in the future. FUNDING: Global Panel on Agriculture and Food Systems for Nutrition and Wellcome Trust.

Air quality-related health damages of food.

Agriculture is a major contributor to air pollution, the largest environmental risk factor for mortality in the United States and worldwide. It is largely unknown, however, how individual foods or entire diets affect human health via poor air quality. We show how food production negatively impacts human health by increasing atmospheric fine particulate matter (PM2.5), and we identify ways to reduce these negative impacts of agriculture. We quantify the air quality-related health damages attributable to 95 agricultural commodities and 67 final food products, which encompass >99% of agricultural production in the United States. Agricultural production in the United States results in 17,900 annual air quality-related deaths, 15,900 of which are from food production. Of those, 80% are attributable to animal-based foods, both directly from animal production and indirectly from growing animal feed. On-farm interventions can reduce PM2.5-related mortality by 50%, including improved livestock waste management and fertilizer application practices that reduce emissions of ammonia, a secondary PM2.5 precursor, and improved crop and animal production practices that reduce primary PM2.5 emissions from tillage, field burning, livestock dust, and machinery. Dietary shifts toward more plant-based foods that maintain protein intake and other nutritional needs could reduce agricultural air quality-related mortality by 68 to 83%. In sum, improved livestock and fertilization practices, and dietary shifts could greatly decrease the health impacts of agriculture caused by its contribution to reduced air quality.

Global food system emissions could preclude achieving the 1.5° and 2°C climate change targets.

The Paris Agreement's goal of limiting the increase in global temperature to 1.5° or 2°C above preindustrial levels requires rapid reductions in greenhouse gas emissions. Although reducing emissions from fossil fuels is essential for meeting this goal, other sources of emissions may also preclude its attainment. We show that even if fossil fuel emissions were immediately halted, current trends in global food systems would prevent the achievement of the 1.5°C target and, by the end of the century, threaten the achievement of the 2°C target. Meeting the 1.5°C target requires rapid and ambitious changes to food systems as well as to all nonfood sectors. The 2°C target could be achieved with less-ambitious changes to food systems, but only if fossil fuel and other nonfood emissions are eliminated soon.

Effectiveness of adjuvant FOLFOX vs 5FU/LV in adults over age 65 with stage II and III colon cancer using a novel hybrid approach.

PURPOSE: Estimates of cancer therapy effects can differ in clinical trials and clinical practice, partly due to underrepresentation of certain patient subgroups in trials. We utilize a hybrid approach, combining clinical trial and real-world data, to estimate the comparative effectiveness of two adjuvant chemotherapy regimens for colon cancer. METHODS: We identified patients aged 66 and older enrolled in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer. Similar patients were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, initiating adjuvant chemotherapy with either 5-fluorouracil (5FU) alone or in combination with oxaliplatin (FOLFOX). We used logistic regression to estimate the likelihood of trial enrollment as a function of age, sex, and substage. Using inverse odds of sampling weights (IOSW), we compared 5-year mortality in patients randomized to FOLFOX vs 5FU using weighted Cox proportional hazards regression, the Nelson-Aalen estimator for cumulative hazards, and bootstrapping for 95% confidence intervals (CIs). RESULTS: There were 690 trial participants and 3834 SEER-Medicare patients. The SEER-Medicare population was older and had a higher proportion of stage IIIB and IIIC patients than the trial. After controlling for differences between populations, the IOSW 5-year HR was 1.21 (0.89, 1.65), slightly farther from the null than the trial estimate (HR = 1.14, 95%CI: 0.87, 1.49). CONCLUSIONS: This study supports mounting evidence of little to no incremental reduction in 5-year mortality for FOLFOX vs 5FU in older adults with stage II-III colon cancer, emphasizing the importance of combining clinical trial and real-world data to support such conclusions.

The healthiness and sustainability of national and global food based dietary guidelines: modelling study.

OBJECTIVE: To analyse the health and environmental implications of adopting national food based dietary guidelines (FBDGs) at a national level and compared with global health and environmental targets. DESIGN: Modelling study. SETTING: 85 countries. PARTICIPANTS: Population of 85 countries. MAIN OUTCOME MEASURES: A graded coding method was developed and used to extract quantitative recommendations from 85 FBDGs. The health and environmental impacts of these guidelines were assessed by using a comparative risk assessment of deaths from chronic diseases and a set of country specific environmental footprints for greenhouse gas emissions, freshwater use, cropland use, and fertiliser application. For comparison, the impacts of adopting the global dietary recommendations of the World Health Organization and the EAT-Lancet Commission on Healthy Diets from Sustainable Food Systems were also analysed. Each guideline's health and sustainability implications were assessed by modelling its adoption at both the national level and globally, and comparing the impacts to global health and environmental targets, including the Action Agenda on Non-Communicable Diseases, the Paris Climate Agreement, the Aichi biodiversity targets related to land use, and the sustainable development goals and planetary boundaries related to freshwater use and fertiliser application. RESULTS: Adoption of national FBDGs was associated with reductions in premature mortality of 15% on average (95% uncertainty interval 13% to 16%) and mixed changes in environmental resource demand, including a reduction in greenhouse gas emissions of 13% on average (regional range -34% to 35%). When universally adopted globally, most of the national guidelines (83, 98%) were not compatible with at least one of the global health and environmental targets. About a third of the FBDGs (29, 34%) were incompatible with the agenda on non-communicable diseases, and most (57 to 74, 67% to 87%) were incompatible with the Paris Climate Agreement and other environmental targets. In comparison, adoption of the WHO recommendations was associated with similar health and environmental changes, whereas adoption of the EAT-Lancet recommendations was associated with 34% greater reductions in premature mortality, more than three times greater reductions in greenhouse gas emissions, and general attainment of the global health and environmental targets. As an example, the FBDGs of the UK, US, and China were incompatible with the climate change, land use, freshwater, and nitrogen targets, and adopting guidelines in line with the EAT-Lancet recommendation could increase the number of avoided deaths from 78 000 (74 000 to 81 000) to 104 000 (96 000 to 112 000) in the UK, from 480 000 (445 000 to 516 000) to 585 000 (523 000 to 646 000) in the USA, and from 1 149 000 (1 095 000 to 1 204 000) to 1 802 000 (1 664 000 to 1 941 000) in China. CONCLUSIONS: This analysis suggests that national guidelines could be both healthier and more sustainable. Providing clearer advice on limiting in most contexts the consumption of animal source foods, in particular beef and dairy, was found to have the greatest potential for increasing the environmental sustainability of dietary guidelines, whereas increasing the intake of whole grains, fruits and vegetables, nuts and seeds, and legumes, reducing the intake of red and processed meat, and highlighting the importance of attaining balanced energy intake and weight levels were associated with most of the additional health benefits. The health results were based on observational data and assuming a causal relation between dietary risk factors and health outcomes. The certainty of evidence for these relations is mostly graded as moderate in existing meta-analyses.

Multiple health and environmental impacts of foods.

Food choices are shifting globally in ways that are negatively affecting both human health and the environment. Here we consider how consuming an additional serving per day of each of 15 foods is associated with 5 health outcomes in adults and 5 aspects of agriculturally driven environmental degradation. We find that while there is substantial variation in the health outcomes of different foods, foods associated with a larger reduction in disease risk for one health outcome are often associated with larger reductions in disease risk for other health outcomes. Likewise, foods with lower impacts on one metric of environmental harm tend to have lower impacts on others. Additionally, of the foods associated with improved health (whole grain cereals, fruits, vegetables, legumes, nuts, olive oil, and fish), all except fish have among the lowest environmental impacts, and fish has markedly lower impacts than red meats and processed meats. Foods associated with the largest negative environmental impacts-unprocessed and processed red meat-are consistently associated with the largest increases in disease risk. Thus, dietary transitions toward greater consumption of healthier foods would generally improve environmental sustainability, although processed foods high in sugars harm health but can have relatively low environmental impacts. These findings could help consumers, policy makers, and food companies to better understand the multiple health and environmental implications of food choices.

Diagnostic Assessment of Assumptions for External Validity: An Example Using Data in Metastatic Colorectal Cancer.

BACKGROUND: Methods developed to estimate intervention effects in external target populations assume that all important effect measure modifiers have been identified and appropriately modeled. Propensity score-based diagnostics can be used to assess the plausibility of these assumptions for weighting methods. METHODS: We demonstrate the use of these diagnostics when assessing the transportability of treatment effects from the standard of care for metastatic colorectal cancer control arm in a phase III trial (HORIZON III) to a target population of 1,942 Medicare beneficiaries age 65+ years. RESULTS: In an unadjusted comparison, control arm participants had lower mortality compared with target population patients treated with the standard of care therapy (trial vs. target hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.58, 0.89). Applying inverse odds of sampling weights attenuated the trial versus target HR (weighted HR = 0.96, 95% CI = 0.73, 1.26). However, whether unadjusted or weighted, hazards did not appear proportional. At 6 months of follow-up, mortality was lower in the weighted trial population than the target population (weighted trial vs. target risk difference [RD] = -0.07, 95% CI = -0.13, -0.01), but not at 12 months (weighted RD = 0.00, 95% CI = -0.09, 0.09). CONCLUSION: These diagnostics suggest that direct transport of treatment effects from HORIZON III to the Medicare population is not valid. However, the proposed sampling model might allow valid transport of the treatment effects on longer-term mortality from HORIZON III to the Medicare population treated in clinical practice. See video abstract at, http://links.lww.com/EDE/B435.

A Cost-Effective Technique for Spinal Instrumentation in the Treatment of Adolescent Idiopathic Scoliosis.

Surgical treatment for adolescent idiopathic scoliosis (AIS) has evolved over the past decades to the point where instrumented arthrodesis with all pedicle screw and rod constructs is commonplace. Although these constructs provide superb correction and fixation, their financial burden is substantial. Here, we present a more cost-effective technique using a combination of pedicle screws (serving as the construct base), a sagittal precontoured unit rod, and sublaminar wires to provide segmental correction for the surgical treatment of AIS. Retrospective analyses of 42 patients treated with this construct were reviewed with a minimum 2-year follow-up. Correction in both coronal and sagittal planes was assessed radiographically and blood loss, operative time, complications, and cost were reviewed from hospital records. We conclude that this technique provides comparable correction to all pedicle screw constructs with similar blood loss and operative time, but with substantially decreased implant cost. The mean implant cost was $8910.83 ± $184.26.

Muscle strength and flexibility characteristics of people displaying excessive medial knee displacement.

OBJECTIVE: To determine differences in strength and range of motion (ROM) between participants who exhibit medial knee displacement (MKD) during a squat that is corrected by a heel lift and those who do not. DESIGN: Case control. SETTING: Sports medicine research laboratory. PARTICIPANTS: Thirty-seven healthy subjects (control, 19; MKD, 18) with no lower-extremity injury in the past 6 months volunteered to participate. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Peak force was measured in newtons using a hand-held dynamometer and passive ROM was measured in degrees with a goniometer. Separate multivariate analyses of variance were used to determine differences in strength and ROM between groups. Post hoc testing was used to elucidate differences between groups. RESULTS: The MKD group had the following: greater hip external rotation strength (P=.03), increased hip extension strength (P=.01), less plantarflexion strength (P=.007), and increased hip external rotation ROM (P=.008). CONCLUSIONS: The MKD group exhibited tight and weak ankle musculature. Interventions focusing on improving strength and ROM of the ankle may improve kinematics during a squat.

Active Galpha(q) subunits and M3 acetylcholine receptors promote distinct modes of association of RGS2 with the plasma membrane.

RGS proteins accelerate the GTPase activity of heterotrimeric G proteins at the plasma membrane. Association of RGS proteins with the plasma membrane can be mediated by interactions with other membrane proteins and by direct interactions with the lipid bilayer. Here we use fluorescence recovery after photobleaching (FRAP) to characterize interactions between RGS2 and M3 acetylcholine receptors (M3Rs), Galpha subunits and the lipid bilayer. Active Galpha(q) and M3Rs both recruited RGS2-EGFP to the plasma membrane. RGS2-EGFP remained bound to the plasma membrane between interactions with active Galpha(q), but rapidly exchanged between membrane-associated and cytosolic pools when recruited by M3Rs.

Endogenous regulator of G-protein signaling proteins regulate the kinetics of Galphaq/11-mediated modulation of ion channels in central nervous system neurons.

Slow synaptic potentials are generated when metabotropic G-protein-coupled receptors activate heterotrimeric G-proteins, which in turn modulate ion channels. Many neurons generate excitatory postsynaptic potentials mediated by G-proteins of the Galphaq/11 family, which in turn activate phospholipase C-beta. Accessory GTPase-activating proteins (GAPs) are thought to be required to accelerate GTP hydrolysis and rapidly turn off G-proteins, but the involvement of GAPs in neuronal Galphaq/11 signaling has not been examined. Here, we show that regulator of G-protein signaling (RGS) proteins provide necessary GAP activity at neuronal Galphaq/11 subunits. We reconstituted inhibition of native 2-pore domain potassium channels in cerebellar granule neurons by expressing chimeric Galpha subunits that are activated by Galphai/o-coupled receptors, thus bypassing endogenous Galphaq/11 subunits. RGS-insensitive variants of these chimeras mediated inhibition of potassium channels that developed and recovered more slowly than inhibition mediated by RGS-sensitive (wild-type) chimeras or native Galphaq/11 subunits. These changes were not accompanied by a change in agonist sensitivity, as might be expected if RGS proteins acted primarily as effector antagonists. The slowed recovery from potassium channel inhibition was largely reversed by an additional mutation that mimics the RGS-bound state. These results suggest that endogenous RGS proteins regulate the kinetics of rapid Galphaq/11-mediated signals in central nervous system neurons by providing GAP activity.

Endogenous RGS proteins regulate presynaptic and postsynaptic function: functional expression of RGS-insensitive Galpha subunits in central nervous system neurons.

Regulators of G-protein signaling (RGS)-insensitive (RGSi) G-protein alpha subunits can be used to indirectly determine the function of endogenous RGS proteins in native cells. This article describes the application of RGSi Galpha subunits to the study of endogenous RGS function in central nervous system (CNS) neurons. Presynaptic inhibition of neurotransmitter release was reconstituted in primary neurons using RGSi Galpha(i/o) subunits, whereas postsynaptic regulation of potassium channels was reconstituted using RGSi chimeras of Galpha(q) and Galpha(i). These studies have shown that endogenous RGS proteins are essential for the rapid termination of some G-protein-mediated signals in CNS neurons, whereas these proteins are much less important for the regulation of other signals. Together, these techniques have helped reveal the complexity of RGS regulation of CNS function.

Dopamine receptor agonists differ in their actions on cardiac ion channels.

Four dopamine receptor agonists used for the treatment of Parkinson's disease (apomorphine, pergolide, ropinirole and sumanirole) were evaluated for the ability to block human ether-a-go-go related gene (hERG) K(+) channels and to modify the duration of canine Purkinje fiber action potentials. Apomorphine, pergolide and ropinirole blocked the hERG-mediated currents with IC(50) values of 2.4, 0.12 and 1.2 microM, respectively. When evaluated in an action potential duration assay, pergolide significantly shortened action potential duration at 90% repolarization (APD(90)) whereas apomorphine and ropinirole significantly prolonged repolarization. Sumanirole only partially blocked hERG K(+) channels at the highest tested concentration (10 microM) and did not modify action potential duration over the tested concentration range (0.65-65 microM). Taken together, these data provide evidence that dopamine receptor agonists developed for the treatment of Parkinson's disease differentially influence hERG K(+) channel function and cardiac action potential duration.

Catastrophic desert formation in Daisyworld.

Feedback between life and its environment is ubiquitous but the strength of coupling and its global implications remain hotly debated. Abrupt changes in the abundance of life for small changes in forcing provide one indicator of regulation, for example, when vegetation-climate feedback collapses in the formation of a desert. Here we use a two-dimensional "Daisyworld" model with curvature to show that catastrophic collapse of life under gradual forcing provides a testable indicator of environmental feedback. When solar luminosity increases to a critical value, a desert forms across a wide band of the planet. The scale of collapse depends on the strength of feedback. The efficiency of temperature regulation is limited by mutation rate in an analogous manner to the limitation of adaptive fitness in evolutionary theories. The final state of the system emerging from single-site rules can be described by two global quantities: optimization of temperature regulation and maximization of diversity, which are mathematically analogous to energy and entropy in thermodynamics.

Factors affecting levels of physical activity in adults.

A large proportion of adults in Western cultures are physically inactive, despite several decades of warnings about the potentially negative health consequences of a sedentary lifestyle. Efforts to promote physical activity have focused on identifying its determinants and designing interventions that might effectively promote regular physical activity. The multitude of factors that induce adults to initiate and maintain programmes of physical activity have been divided into those that are invariable (age, gender, race, ethnicity) and those that are presumed to be modifiable (behavioural and personality characteristics, environmental circumstances and community settings). The lack of consistency in the design, analysis and reporting of interventions in the lives of inactive or sedentary individuals has produced equivocal results. However, several social and environmental factors have systematically emerged as determinants of physical activity in adults. In ethnic minorities, the removal of barriers such as unaffordable facilities and unavailable childcare, high crime rates, fear for personal safety and culturally inappropriate activities are of primary importance. Social support from family, peers, communities and healthcare providers has resulted in modest improvements across cultures, ages and genders in selected settings, but the definition of specific interventions and their outcomes deserve additional attention. Longitudinal studies indicate that components of physical fitness are relatively transitory, with low to modest correlations between physical activity and measures of physical fitness in childhood and adolescence and in adulthood. Attempts to explain the activity behaviour of adults by applying various theories in programmes of intervention have also produced mixed results. Successful interventions tailor programmes to individual needs, account for personal levels of fitness, allow for personal control of the activity and its outcomes, and provide for social support by family, peers and communities. The initiation and maintenance of regular physical activity in adults depends on a multitude of biological and sociocultural variables that demand attention across the lifespan.