Showing papers by "Dartmouth College published in 2021"

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline.

Abstract: Introduction:This guideline establishes clinical practice recommendations for the use of behavioral and psychological treatments for chronic insomnia disorder in adults.Methods:The American Academy...

The L-functions and modular forms database

Abstract: The LMFDB is a database of mathematical objects and the connections between them. A web interface allows visitors to browse and query the database in a flexible and powerful way. At the core of the LMFDB is the Langlands program (see Figure 1), a set of conjectures relating objects from arithmetic algebraic geometry (such as number fields, elliptic curves, and abelian varieties) with modular and automorphic forms via Galois representations and Lfunctions (the most basic of which is the Riemann zeta function). The LMFDB catalogs these objects and the ways in which they link to one another, as well as other closely related objects like permutation groups and p-adic fields. Currently, the LMFDB includes tens of millions of objects totalling over 4.8 terabytes of data. Hosted on Google Cloud Platform, in 2020, it was used by more than 30 000 users in 146

SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting.

Abstract: The COVID-19 pandemic has claimed the lives of nearly 2 million people worldwide.1 Following rapid sequencing of SARS-CoV-2, pharmaceutical companies and academic institutions rapidly generated vaccine candidates on the back of a variety of both established and novel vaccine platforms.2–4 Vaccines accelerated at unprecedented pace to phase 3 development, and in December 2020, two mRNA vaccines and one inactivated vaccine were authorised for use in a number of countries. Additional vaccine platforms and candidates are in late stages of phase 3 testing.5 Prioritisation of vaccine access is generally determined by regional health authorities on the basis of risk of SARS-CoV-2 exposure and risk of developing complications from COVID-19 in order to equitably protect and promote global public well-being.6–8 IBD, including Crohn’s disease and ulcerative colitis, are characterised by chronic intestinal inflammation due to immune dysregulation. IBD is often treated with immune-modifying therapies including corticosteroids, immunomodulators, biologic agents including monoclonal antibody inhibitors of tumour necrosis factor (TNF) alpha, interleukin 12/23, integrins and small molecules such as Janus kinase (JAK) inhibitors. Prior studies have evaluated the safety and effectiveness of various vaccines in patients with IBD, with specific focus on the impact of immune-modifying therapies on serologic responses. In general, non-live vaccines are considered safe in patients with IBD regardless of IBD therapy, although those on specific types of immune-modifying treatments at the time of vaccination may have reduced vaccine immune responses.9–12 In spite of decreased efficacy associated with immune-modifying medication, most vaccines are broadly recommended for those with IBD.13–15 Patients with immune conditions (including IBD) were excluded from the SARS-CoV-2 vaccine clinical development programmes,16 and novel vaccine platforms not previously studied in IBD populations are now authorised in many countries. Therefore, many questions regarding the safety and effectiveness of SARS-CoV-2 vaccination in patients with …

The TESS Objects of Interest Catalog from the TESS Prime Mission

Abstract: We present 2241 exoplanet candidates identified with data from the Transiting Exoplanet Survey Satellite (TESS) during its 2 yr Prime Mission. We list these candidates in the TESS Objects of Interest (TOI) Catalog, which includes both new planet candidates found by TESS and previously known planets recovered by TESS observations. We describe the process used to identify TOIs, investigate the characteristics of the new planet candidates, and discuss some notable TESS planet discoveries. The TOI catalog includes an unprecedented number of small planet candidates around nearby bright stars, which are well suited for detailed follow-up observations. The TESS data products for the Prime Mission (sectors 1-26), including the TOI catalog, light curves, full-frame images, and target pixel files, are publicly available at the Mikulski Archive for Space Telescopes.

Global prevalence of non-perennial rivers and streams

Abstract: Flowing waters have a unique role in supporting global biodiversity, biogeochemical cycles and human societies1–5. Although the importance of permanent watercourses is well recognized, the prevalence, value and fate of non-perennial rivers and streams that periodically cease to flow tend to be overlooked, if not ignored6–8. This oversight contributes to the degradation of the main source of water and livelihood for millions of people5. Here we predict that water ceases to flow for at least one day per year along 51–60 per cent of the world’s rivers by length, demonstrating that non-perennial rivers and streams are the rule rather than the exception on Earth. Leveraging global information on the hydrology, climate, geology and surrounding land cover of the Earth’s river network, we show that non-perennial rivers occur within all climates and biomes, and on every continent. Our findings challenge the assumptions underpinning foundational river concepts across scientific disciplines9. To understand and adequately manage the world’s flowing waters, their biodiversity and functional integrity, a paradigm shift is needed towards a new conceptual model of rivers that includes flow intermittence. By mapping the distribution of non-perennial rivers and streams, we provide a stepping-stone towards addressing this grand challenge in freshwater science. Non-perennial rivers and streams are mapped globally, showing that more than half of rivers worldwide experience no flow for at least one day per year.

Quantitative image analysis of microbial communities with BiofilmQ

Abstract: Biofilms are microbial communities that represent a highly abundant form of microbial life on Earth. Inside biofilms, phenotypic and genotypic variations occur in three-dimensional space and time; microscopy and quantitative image analysis are therefore crucial for elucidating their functions. Here, we present BiofilmQ-a comprehensive image cytometry software tool for the automated and high-throughput quantification, analysis and visualization of numerous biofilm-internal and whole-biofilm properties in three-dimensional space and time.

Decolonizing Global Health Education: Rethinking Institutional Partnerships and Approaches.

Abstract: Global health often entails partnerships between institutions in low- and middle-income countries (LMICs) that were previously colonized and high-income countries (HICs) that were colonizers. Little attention has been paid to the legacy of former colonial relationships and the influence they have on global health initiatives. There have been recent calls for the decolonization of global health education and the reexamination of assumptions and practices under pinning global health partnerships. Medicine's role in colonialism cannot be ignored and requires critical review. There is a growing awareness of how knowledge generated in HICs defines practices and informs thinking to the detriment of knowledge systems in LMICs. Additionally, research partnerships often benefit the better-resourced partner. In this article, the authors offer a brief analysis of the intersections between colonialism, medicine, and global health education and explore the lingering impact of colonialist legacies on current global health programs and partnerships. They describe how "decolonized" perspectives have not gained sufficient traction and how inequitable power dynamics and neocolonialist assumptions continue to dominate. They discuss 5 approaches, and highlight resources, that challenge colonial paradigms in the global health arena. Furthermore, they argue for the inclusion of more transfor mative learning approaches to promote change in attitudes and practice. They call for critical reflection and concomitant action to shift colonial paradigms toward more equitable partnerships in global education.

Is happiness U-shaped everywhere? Age and subjective well-being in 145 countries

Abstract: A large empirical literature has debated the existence of a U-shaped happiness-age curve. This paper re-examines the relationship between various measures of well-being and age in 145 countries, including 109 developing countries, controlling for education and marital and labor force status, among others, on samples of individuals under the age of 70. The U-shape of the curve is forcefully confirmed, with an age minimum, or nadir, in midlife around age 50 in separate analyses for developing and advanced countries as well as for the continent of Africa. The happiness curve seems to be everywhere. While panel data are largely unavailable for this issue, and the findings using such data largely confirm the cross-section results, the paper discusses insights on why cohort effects do not drive the findings. I find the age of the minima has risen over time in Europe and the USA.

Cannabis use and cannabis use disorder

Abstract: Cannabis use disorder (CUD) is an underappreciated risk of using cannabis that affects ~10% of the 193 million cannabis users worldwide. The individual and public health burdens are less than those of other forms of drug use, but CUD accounts for a substantial proportion of persons seeking treatment for drug use disorders owing to the high global prevalence of cannabis use. Cognitive behavioural therapy, motivational enhancement therapy and contingency management can substantially reduce cannabis use and cannabis-related problems, but enduring abstinence is not a common outcome. No pharmacotherapies have been approved for cannabis use or CUD, although a number of drug classes (such as cannabinoid agonists) have shown promise and require more rigorous evaluation. Treatment of cannabis use and CUD is often complicated by comorbid mental health and other substance use disorders. The legalization of non-medical cannabis use in some high-income countries may increase the prevalence of CUD by making more potent cannabis products more readily available at a lower price. States that legalize medical and non-medical cannabis use should inform users about the risks of CUD and provide information on how to obtain assistance if they develop cannabis-related mental and/or physical health problems.

Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment

Abstract: Introduction:The purpose of this systematic review is to provide supporting evidence for a clinical practice guideline on the use of behavioral and psychological treatments for chronic insomnia dis...

A Survey of Data Augmentation Approaches for NLP

Abstract: Data augmentation has recently seen increased interest in NLP due to more work in low-resource domains, new tasks, and the popularity of large-scale neural networks that require large amounts of training data. Despite this recent upsurge, this area is still relatively underexplored, perhaps due to the challenges posed by the discrete nature of language data. In this paper, we present a comprehensive and unifying survey of data augmentation for NLP by summarizing the literature in a structured manner. We first introduce and motivate data augmentation for NLP, and then discuss major methodologically representative approaches. Next, we highlight techniques that are used for popular NLP applications and tasks. We conclude by outlining current challenges and directions for future research. Overall, our paper aims to clarify the landscape of existing literature in data augmentation for NLP and motivate additional work in this area. We also present a GitHub repository with a paper list that will be continuously updated at this https URL

Debaryomyces is enriched in Crohn’s disease intestinal tissue and impairs healing in mice

Abstract: Alterations of the mycobiota composition associated with Crohn’s disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch’s postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell–specific type 1 interferon–CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.

Trinity of relational quantum dynamics

Abstract: The problem of time in quantum gravity calls for a relational solution. Using quantum reduction maps, we establish a previously unknown equivalence between three approaches to relational quantum dynamics: (1) relational observables in the clock-neutral picture of Dirac quantization, (2) Page and Wootters' (PW) Schr\"odinger picture formalism, and (3) the relational Heisenberg picture obtained via symmetry reduction. Constituting three faces of the same dynamics, we call this equivalence the trinity. In the process, we develop a quantization procedure for relational Dirac observables using covariant positive operator-valued measures which encompass nonideal clocks and resolve the nonmonotonicity issue of realistic quantum clocks reported by Unruh and Wald. The quantum reduction maps reveal this procedure as the quantum analog of gauge-invariantly extending gauge-fixed quantities. We establish algebraic properties of these relational observables. We extend a recent ``clock-neutral'' approach to changing temporal reference frames, transforming relational observables and states, and demonstrate a clock dependent temporal nonlocality effect. We show that Kucha\ifmmode \check{r}\else \v{r}\fi{}'s criticism, alleging that the conditional probabilities of the PW formalism violate the constraint, is incorrect. They are a quantum analog of a gauge-fixed description of a gauge-invariant quantity and equivalent to the manifestly gauge-invariant evaluation of relational observables in the physical inner product. The trinity furthermore resolves a previously reported normalization ambiguity and clarifies the role of entanglement in the PW formalism. The trinity finally permits us to resolve Kucha\ifmmode \check{r}\else \v{r}\fi{}'s criticism that the PW formalism yields wrong propagators by showing how conditional probabilities of relational observables give the correct transition probabilities. Unlike previous proposals, our resolution does not invoke approximations, ideal clocks or ancilla systems, is manifestly gauge invariant, and easily extends to an arbitrary number of conditionings.

Rethinking peripheral T cell tolerance: checkpoints across a T cell's journey.

Abstract: Following their exit from the thymus, T cells are endowed with potent effector functions but must spare host tissue from harm. The fate of these cells is dictated by a series of checkpoints that regulate the quality and magnitude of T cell-mediated immunity, known as tolerance checkpoints. In this Perspective, we discuss the mediators and networks that control the six main peripheral tolerance checkpoints throughout the life of a T cell: quiescence, ignorance, anergy, exhaustion, senescence and death. At the naive T cell stage, two intrinsic checkpoints that actively maintain tolerance are quiescence and ignorance. In the presence of co-stimulation-deficient T cell activation, anergy is a dominant hallmark that mandates T cell unresponsiveness. When T cells are successfully stimulated and reach the effector stage, exhaustion and senescence can limit excessive inflammation and prevent immunopathology. At every stage of the T cell's journey, cell death exists as a checkpoint to limit clonal expansion and to terminate unrestrained responses. Here, we compare and contrast the T cell tolerance checkpoints and discuss their specific roles, with the aim of providing an integrated view of T cell peripheral tolerance and fate regulation.

InterCarb: A Community Effort to Improve Interlaboratory Standardization of the Carbonate Clumped Isotope Thermometer Using Carbonate Standards.

Abstract: Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth-system processes. However, interlaboratory discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I-CDES) values for Intercarb-Carbon Dioxide Equilibrium Scale.

A neuroimaging biomarker for sustained experimental and clinical pain

Abstract: Sustained pain is a major characteristic of clinical pain disorders, but it is difficult to assess in isolation from co-occurring cognitive and emotional features in patients. In this study, we developed a functional magnetic resonance imaging signature based on whole-brain functional connectivity that tracks experimentally induced tonic pain intensity and tested its sensitivity, specificity and generalizability to clinical pain across six studies (total n = 334). The signature displayed high sensitivity and specificity to tonic pain across three independent studies of orofacial tonic pain and aversive taste. It also predicted clinical pain severity and classified patients versus controls in two independent studies of clinical low back pain. Tonic and clinical pain showed similar network-level representations, particularly in somatomotor, frontoparietal and dorsal attention networks. These patterns were distinct from representations of experimental phasic pain. This study identified a brain biomarker for sustained pain with high potential for clinical translation. The functional magnetic resonance imaging connectivity pattern of tonic experimental orofacial pain can be used as a quantitative and unbiased biomarker of clinical pain.

A gene–environment-induced epigenetic program initiates tumorigenesis

Abstract: Tissue damage increases the risk of cancer through poorly understood mechanisms1 In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3 Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an ‘acinar-to-neoplasia’ chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation Collectively, our study demonstrates how gene–environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer In mouse models of pancreatic cancer, a cooperative interaction between tissue damage and Kras gene mutation rapidly induces cancer-associated chromatin states in pre-malignant tissue, leading to gene dysregulation and neoplastic transformation

Transcriptomic organization of the human brain in post-traumatic stress disorder.

Abstract: Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.

E-cigarette use and respiratory disorders: an integrative review of converging evidence from epidemiological and laboratory studies.

Abstract: Background Use of electronic cigarettes (e-cigarettes) is prevalent among adolescents and young adults, but there has been limited knowledge about health consequences in human populations. We conduct a systematic review and meta-analysis of results on respiratory disorders from studies of general-population samples and consider the mapping of these results to findings about biological processes linked to e-cigarettes in controlled laboratory studies. Method We conducted a literature search and meta-analysis of epidemiological studies on the association of e-cigarette use with asthma and with COPD. We discuss findings from laboratory studies about effects of e-cigarettes on four biological processes: cytotoxicity, oxidative stress/inflammation, susceptibility to infection and genetic expression. Results Epidemiological studies, both cross-sectional and longitudinal, show a significant association of e-cigarette use with asthma and COPD, controlling for cigarette smoking and other covariates. For asthma (n=15 studies), the pooled adjusted odds ratio (aOR) was 1.39 (95% CI 1.28–1.51); for COPD (n=9 studies) the aOR was 1.49 (95% CI 1.36–1.65). Laboratory studies consistently show an effect of e-cigarettes on biological processes related to respiratory harm and susceptibility to illness, with e-cigarette conditions differing significantly from clean-air controls, although sometimes less than for cigarettes. Conclusions The evidence from epidemiological studies meets established criteria for consistency, strength of effect, temporality, and in some cases a dose–response gradient. Biological plausibility is indicated by evidence from multiple laboratory studies. We conclude that e-cigarette use has consequences for asthma and COPD, which is of concern for respirology and public health.

A systematic review of rehabilitation and exercise recommendations in oncology guidelines

Abstract: Guidelines promote high quality cancer care. Rehabilitation recommendations in oncology guidelines have not been characterized and may provide insight to improve integration of rehabilitation into oncology care. This report was developed as a part of the World Health Organization (WHO) Rehabilitation 2030 initiative to identify rehabilitation-specific recommendations in guidelines for oncology care. A systematic review of guidelines was conducted. Only guidelines published in English, for adults with cancer, providing recommendations for rehabilitation referral and assessment or interventions between 2009 and 2019 were included. 13840 articles were identified. After duplicates and applied filters, 4897 articles were screened. 69 guidelines were identified with rehabilitation-specific recommendations. Thirty-seven of the 69 guidelines endorsed referral to rehabilitation services but provided no specific recommendations regarding assessment or interventions. Thirty-two of the 69 guidelines met the full inclusion criteria and were assessed using the AGREE II tool. Twenty-one of these guidelines achieved an AGREE II quality score of ≥ 45 and were fully extracted. Guidelines exclusive to pharmacologic interventions and complementary and alternative interventions were excluded. Findings identify guidelines that recommend rehabilitation services across many cancer types and for various consequences of cancer treatment signifying that rehabilitation is a recognized component of oncology care. However, these findings are at odds with clinical reports of low rehabilitation utilization rates suggesting that guideline recommendations may be overlooked. Considering that functional morbidity negatively affects a majority of cancer survivors, improving guideline concordant rehabilitative care could have substantial impact on function and quality of life among cancer survivors.

What Is Your Estimand? Defining the Target Quantity Connects Statistical Evidence to Theory

Abstract: We make only one point in this article. Every quantitative study must be able to answer the question: what is your estimand? The estimand is the target quantity—the purpose of the statistical analy...

Expanding controlled donation after the circulatory determination of death: statement from an international collaborative.

Abstract: A decision to withdraw life-sustaining treatment (WLST) is derived by a conclusion that further treatment will not enable a patient to survive or will not produce a functional outcome with acceptable quality of life that the patient and the treating team regard as beneficial. Although many hospitalized patients die under such circumstances, controlled donation after the circulatory determination of death (cDCDD) programs have been developed only in a reduced number of countries. This International Collaborative Statement aims at expanding cDCDD in the world to help countries progress towards self-sufficiency in transplantation and offer more patients the opportunity of organ donation. The Statement addresses three fundamental aspects of the cDCDD pathway. First, it describes the process of determining a prognosis that justifies the WLST, a decision that should be prior to and independent of any consideration of organ donation and in which transplant professionals must not participate. Second, the Statement establishes the permanent cessation of circulation to the brain as the standard to determine death by circulatory criteria. Death may be declared after an elapsed observation period of 5 min without circulation to the brain, which confirms that the absence of circulation to the brain is permanent. Finally, the Statement highlights the value of perfusion repair for increasing the success of cDCDD organ transplantation. cDCDD protocols may utilize either in situ or ex situ perfusion consistent with the practice of each country. Methods to accomplish the in situ normothermic reperfusion of organs must preclude the restoration of brain perfusion to not invalidate the determination of death.

Does Conjoint Analysis Mitigate Social Desirability Bias

Abstract: How can we elicit truthful responses in surveys? Political scientists are often concerned about systematic survey misreporting on sensitive topics, known as social desirability bias (SDB). Conjoint analysis has become a popular tool to address this concern, despite the lack of systematic evidence showing its suitability for this purpose. We employ a novel experimental design to identify a fully randomized conjoint design's ability to mitigate SDB. Specifically, we compare a standard conjoint design against a partially randomized design where only the sensitive attribute is varied between two profiles in each task. Our design also includes a placebo condition designed to remove confounding due to the increased attention to the varying attribute under the partially randomized design. We implemented this experiment in a survey to uncover respondents' attitudes toward environmental conservation. We find suggestive evidence that conjoint analysis does, indeed, mitigate SDB.