Inherited blood cancer predisposition through altered transcription elongation.

Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.

Life histories of myeloproliferative neoplasms inferred from phylogenies.

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.

The longitudinal dynamics and natural history of clonal haematopoiesis.

Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Clonal dynamics of haematopoiesis across the human lifespan.

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

Lineage tracing of human development through somatic mutations.

The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.

Convergent somatic mutations in metabolism genes in chronic liver disease.

The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9-13 than in normal liver13-16, which enables positive selection to shape the genomic landscape9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes17-19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.

Band gap opening of metallic single-walled carbon nanotubes via noncovalent symmetry breaking.

Covalent bonding interactions determine the energy-momentum (E-k) dispersion (band structure) of solid-state materials. Here, we show that noncovalent interactions can modulate the E-k dispersion near the Fermi level of a low-dimensional nanoscale conductor. We demonstrate that low energy band gaps may be opened in metallic carbon nanotubes through polymer wrapping of the nanotube surface at fixed helical periodicity. Electronic spectral, chiro-optic, potentiometric, electronic device, and work function data corroborate that the magnitude of band gap opening depends on the nature of the polymer electronic structure. Polymer dewrapping reverses the conducting-to-semiconducting phase transition, restoring the native metallic carbon nanotube electronic structure. These results address a long-standing challenge to develop carbon nanotube electronic structures that are not realized through disruption of π conjugation, and establish a roadmap for designing and tuning specialized semiconductors that feature band gaps on the order of a few hundred meV.

Practical causal mediation analysis: extending nonparametric estimators to accommodate multiple mediators and multiple intermediate confounders.

Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including (i) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be (ii) multivariate, and (iii) the existence of multivariate mediators. All three challenges are present in the mediation analysis we consider here, where our goal is to estimate the indirect effects of receiving a Section 8 housing voucher as a young child on the risk of developing a psychiatric mood disorder in adolescence that operate through mediators related to neighborhood poverty, the school environment, and instability of the neighborhood and school environments, considered together and separately. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no readily implementable nonparametric estimator for IDE/IIE exists that allows for both multivariate mediators and multivariate post-exposure intermediate confounders. The absence of such an IDE/IIE estimator that can easily accommodate both multivariate mediators and post-exposure confounders represents a significant limitation for real-world analyses, because when considering each mediator subgroup separately, the remaining mediator subgroups (or a subset of them) become post-exposure intermediate confounders. We address this gap by extending a recently developed nonparametric estimator for the IDE/IIE to allow for easy incorporation of multivariate mediators and multivariate post-exposure confounders simultaneously. We apply the proposed estimation approach to our analysis, including walking through a strategy to account for other, possibly co-occurring intermediate variables when considering each mediator subgroup separately.

Quantifying inactive lithium in lithium metal batteries.

Lithium metal anodes offer high theoretical capacities (3,860 milliampere-hours per gram)1, but rechargeable batteries built with such anodes suffer from dendrite growth and low Coulombic efficiency (the ratio of charge output to charge input), preventing their commercial adoption2,3. The formation of inactive ('dead') lithium- which consists of both (electro)chemically formed Li+ compounds in the solid electrolyte interphase and electrically isolated unreacted metallic Li0 (refs 4,5)-causes capacity loss and safety hazards. Quantitatively distinguishing between Li+ in components of the solid electrolyte interphase and unreacted metallic Li0 has not been possible, owing to the lack of effective diagnostic tools. Optical microscopy6, in situ environmental transmission electron microscopy7,8, X-ray microtomography9 and magnetic resonance imaging10 provide a morphological perspective with little chemical information. Nuclear magnetic resonance11, X-ray photoelectron spectroscopy12 and cryogenic transmission electron microscopy13,14 can distinguish between Li+ in the solid electrolyte interphase and metallic Li0, but their detection ranges are limited to surfaces or local regions. Here we establish the analytical method of titration gas chromatography to quantify the contribution of unreacted metallic Li0 to the total amount of inactive lithium. We identify the unreacted metallic Li0, not the (electro)chemically formed Li+ in the solid electrolyte interphase, as the dominant source of inactive lithium and capacity loss. By coupling the unreacted metallic Li0 content to observations of its local microstructure and nanostructure by cryogenic electron microscopy (both scanning and transmission), we also establish the formation mechanism of inactive lithium in different types of electrolytes and determine the underlying cause of low Coulombic efficiency in plating and stripping (the charge and discharge processes, respectively, in a full cell) of lithium metal anodes. We propose strategies for making lithium plating and stripping more efficient so that lithium metal anodes can be used for next-generation high-energy batteries.

Learning Optimal Dynamic Treatment Regimes from Longitudinal Data.

Studies often report estimates of the average treatment effect (ATE). While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual's information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule (ODTR). Treatment, however, is typically not limited to a single point in time; consequently, learning an optimal rule for a time-varying treatment may involve not just learning the extent to which the comparative treatments' benefits vary across the characteristics of individuals, but also learning the extent to which the comparative treatments' benefits vary as relevant circumstances evolve within an individual. The goal of this paper is to provide a tutorial for estimating ODTR from longitudinal observational and clinical trial data for applied researchers. We describe an approach that uses a doubly-robust unbiased transformation of the conditional average treatment effect. We then learn a time-varying ODTR for when to increase buprenorphine-naloxone (BUP-NX) dose to minimize return-to-regular-opioid-use among patients with opioid use disorder. Our analysis highlights the utility of ODTRs in the context of sequential decision making: the learned ODTR outperforms a clinically defined strategy.

Aerosol Jet Printing Conductive 3D Microstructures from Graphene Without Post-Processing.

Three-dimensional (3D) graphene microstructures have the potential to boost performance in high-capacity batteries and ultrasensitive sensors. Numerous techniques have been developed to create such structures; however, the methods typically rely on structural supports, and/or lengthy post-print processing, increasing cost and complexity. Additive manufacturing techniques, such as printing, show promise in overcoming these challenges. This study employs aerosol jet printing for creating 3D graphene microstructures using water as the only solvent and without any post-print processing required. The graphene pillars exhibit conductivity immediately after printing, requiring no high-temperature annealing. Furthermore, these pillars are successfully printed in freestanding configurations at angles below 45° relative to the substrate, showcasing their adaptability for tailored applications. When graphene pillars are added to humidity sensors, the additional surface area does not yield a corresponding increase in sensor performance. However, graphene trusses, which add a parallel conduction path to the sensing surface, are found to improve sensitivity nearly 2×, highlighting the advantages of a topologically suspended circuit construction when adding 3D microstructures to sensing electrodes. Overall, incorporating 3D graphene microstructures to sensor electrodes can provide added sensitivity, and aerosol jet printing is a viable path to realizing these conductive microstructures without any post-print processing.

Tachol1 QTL on mouse chromosome 1 is responsible for hypercholesterolemia and diet-induced obesity.

Hypercholesterolemia raises the risk for cardiovascular complications and overall health. Hypercholesterolemia is common, affecting 10% of the general population of the US, and heritable. Most individuals with hypercholesterolemia have a polygenic predisposition to the condition. Previously we identified a quantitative trait locus, Tachol1, linked to hypercholesterolemia on mouse chromosome 1 (Chr1) in a cross between C57BL/6J (B6) and TALLYHO/JngJ (TH) mice, a polygenic model for human obesity, type 2 diabetes and hyperlipidemia. Subsequently, using congenic mice that carry a TH-derived genomic segment of Chr1 on a B6 background, we demonstrated that the distal segment of Chr1, where Tachol1 maps, is necessary to cause hypercholesterolemia, as well as diet-induced obesity. In this study, we generated overlapping subcongenic lines to the distal segment of congenic region and characterized subcongenic mice carrying the smallest TH region of Tachol1, ~ 16.2 Mb in size (B6.TH-Chr1-16.2 Mb). Both male and female B6.TH-Chr1-16.2 Mb mice showed a significantly increased plasma total cholesterol levels compared to B6 on both chow and high fat (HF) diet. B6.TH-Chr1-16.2 Mb mice also had greater fat mass than B6 on HF diet, without increasing food intake. The gene and protein expression levels of absent in melanoma 2 (Aim2) gene were significantly upregulated in B6.TH-Chr1-16.2 Mb mice compared to B6. In summary, we confirmed the effect of Tachol1 on hypercholesterolemia and diet-induced obesity using subcongenic analysis.

Feasibility and acceptability of remotely monitoring spirometry and pulse oximetry as part of interstitial lung disease clinical care: a single arm observational study.

BACKGROUND: Remote monitoring of patient-recorded spirometry and pulse oximetry offers an alternative approach to traditional hospital-based monitoring of interstitial lung disease (ILD). Remote spirometry has been observed to reasonably reflect clinic spirometry in participants with ILD but remote monitoring has not been widely incorporated into clinical practice. We assessed the feasibility of remotely monitoring patients within a clinical ILD service. METHODS: Prospective, single-arm, open-label observational multi-centre study (NCT04850521). Inclusion criteria included ILD diagnosis, age ≥ 18 years, FVC ≥ 50% predicted. 60 participants were asked to record a single spirometry and oximetry measurement at least once daily, monitored weekly by their local clinical team. Feasibility was defined as ≥ 68% of participants with ≥ 70% adherence to study measurements and recording measurements ≥ 3 times/week throughout. RESULTS: A total of 60 participants were included in the analysis. 42/60 (70%) were male; mean age 67.8 years (± 11.2); 34/60 (56.7%) had idiopathic pulmonary fibrosis (IPF), Median ILD-GAP score was 3 (IQR 1-4.75). Spirometry adherence was achieved for ≥ 70% of study days in 46/60 participants (77%) and pulse oximetry adherence in 50/60 participants (83%). Recording ≥ 3 times/week every week was provided for spirometry in 41/60 participants (68%) and pulse oximetry in 43/60 participants (72%). Mean difference between recent clinic and baseline home spirometry was 0.31 L (± 0.72). 85.7% (IQR 63.9-92.6%) home spirometry attempts/patient were acceptable or usable according to ERS/ATS spirometry criteria. Positive correlation was observed between ILD-GAP score and adherence to spirometry and oximetry (rho 0.24 and 0.38 respectively). Adherence of weekly monitoring by clinical teams was 80.95% (IQR 64.19-95.79). All participants who responded to an experience questionnaire (n = 33) found remote measurements easy to perform and 75% wished to continue monitoring their spirometry at the conclusion of the study. CONCLUSION: Feasibility of remote monitoring within an ILD clinical service was demonstrated over 3 months for both daily home spirometry and pulse oximetry of patients. Remote monitoring may be more acceptable to participants who are older or have more advanced disease. TRIAL REGISTRATION: clinicaltrials.gov NCT04850521 registered 20th April 2021.

Independent and joint contributions of physical disability and chronic pain to incident opioid use disorder and opioid overdose among Medicaid patients.

BACKGROUND: Chronic pain has been extensively explored as a risk factor for opioid misuse, resulting in increased focus on opioid prescribing practices for individuals with such conditions. Physical disability sometimes co-occurs with chronic pain but may also represent an independent risk factor for opioid misuse. However, previous research has not disentangled whether disability contributes to risk independent of chronic pain. METHODS: Here, we estimate the independent and joint adjusted associations between having a physical disability and co-occurring chronic pain condition at time of Medicaid enrollment on subsequent 18-month risk of incident opioid use disorder (OUD) and non-fatal, unintentional opioid overdose among non-elderly, adult Medicaid beneficiaries (2016-2019). RESULTS: We find robust evidence that having a physical disability approximately doubles the risk of incident OUD or opioid overdose, and physical disability co-occurring with chronic pain increases the risks approximately sixfold as compared to having neither chronic pain nor disability. In absolute numbers, those with neither a physical disability nor chronic pain condition have a 1.8% adjusted risk of incident OUD over 18 months of follow-up, those with physical disability alone have an 2.9% incident risk, those with chronic pain alone have a 3.6% incident risk, and those with co-occurring physical disability and chronic pain have a 11.1% incident risk. CONCLUSIONS: These findings suggest that those with a physical disability should receive increased attention from the medical and healthcare communities to reduce their risk of opioid misuse and attendant negative outcomes.

Using instrumental variables to address unmeasured confounding in causal mediation analysis.

Mediation analysis is a strategy for understanding the mechanisms by which interventions affect later outcomes. However, unobserved confounding concerns may be compounded in mediation analyses, as there may be unobserved exposure-outcome, exposure-mediator, and mediator-outcome confounders. Instrumental variables (IVs) are a popular identification strategy in the presence of unobserved confounding. However, in contrast to the rich literature on the use of IV methods to identify and estimate a total effect of a non-randomized exposure, there has been almost no research into using IV as an identification strategy to identify mediational indirect effects. In response, we define and nonparametrically identify novel estimands-double complier interventional direct and indirect effects-when 2, possibly related, IVs are available, one for the exposure and another for the mediator. We propose nonparametric, robust, efficient estimators for these effects and apply them to a housing voucher experiment.

Zinc N,N-bis(2-picolyl)amine Chelates Show Substitution-Dependent Cleavage of Phosphodiesters in Models as Well as of PNAzyme-RNA Bulges.

PNAzymes are a group of artificial enzymes which show promising results in selective and efficient cleavage of RNA targets. In the present study, we introduce a series of metal chelating groups based on N,N-bis(2-picolyl) groups (parent, 6-methyl and 6-amino substituted) as the active sites of novel PNAzymes. An improved synthetic route for the 6-amino analogues is described. The catalytic activity of the chelating groups for cleaving phosphodiesters were assessed with the model substrate 2-hydroxypropyl p-nitrophenyl phosphate (HPNPP), confirming that the zinc complexes have the reactivity order of parent < 2-methyl < 2-amino. The three ligands were conjugated to a PNA oligomer to form three PNAzymes which showed the same order of reactivity and some sensitivity to the size of the RNA bulge designed into the catalyst-substrate complex. This work demonstrates that the kinetic activity observed for the model substrate HPNPP could be translated onto the PNAzymes, but that more reactive Zn complexes are required for such PNAzymes to be viable therapeutic agents.

Optimally Choosing Medication Type for Patients With Opioid Use Disorder.

Patients with opioid use disorder (OUD) tend to get assigned to one of 3 medications based on the treatment program to which the patient presents (e.g., opioid treatment programs tend to treat patients with methadone, while office-based practices tend to prescribe buprenorphine). It is possible that optimally matching patients with treatment type would reduce the risk of return to regular opioid use (RROU). We analyzed data from 3 comparative effectiveness trials from the US National Institute on Drug Abuse Clinical Trials Network (CTN0027, 2006-2010; CTN0030, 2006-2009; and CTN0051 2014-2017), in which patients with OUD (n = 1,459) were assigned to treatment with either injection extended-release naltrexone (XR-NTX), sublingual buprenorphine-naloxone (BUP-NX), or oral methadone. We learned an individualized rule by which to assign medication type such that risk of RROU during 12 weeks of treatment would be minimized, and then estimated the amount by which RROU risk could be reduced if the rule were applied. Applying our estimated treatment rule would reduce risk of RROU compared with treating everyone with methadone (relative risk (RR) = 0.79, 95% confidence interval (CI): 0.60, 0.97) or treating everyone with XR-NTX (RR = 0.71, 95% CI: 0.47, 0.96). Applying the estimated treatment rule would have resulted in a similar risk of RROU to that of with treating everyone with BUP-NX (RR = 0.92, 95% CI: 0.73, 1.11).

Mass Spectrometric Analysis of the Active Site Tryptic Peptide of Recombinant O6-Methylguanine-DNA Methyltransferase Following Incubation with Human Colorectal DNA Reveals the Presence of an O6-Alkylguanine Adductome.

Human exposure to DNA alkylating agents is poorly characterized, partly because only a limited range of specific alkyl DNA adducts have been quantified. The human DNA repair protein, O6-methylguanine O6-methyltransferase (MGMT), irreversibly transfers the alkyl group from DNA O6-alkylguanines (O6-alkGs) to an acceptor cysteine, allowing the simultaneous detection of multiple O6-alkG modifications in DNA by mass spectrometric analysis of the MGMT active site peptide (ASP). Recombinant MGMT was incubated with oligodeoxyribonucleotides (ODNs) containing different O6-alkGs, Temozolomide-methylated calf thymus DNA (Me-CT-DNA), or human colorectal DNA of known O6-MethylG (O6-MeG) levels. It was digested with trypsin, and ASPs were detected and quantified by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. ASPs containing S-methyl, S-ethyl, S-propyl, S-hydroxyethyl, S-carboxymethyl, S-benzyl, and S-pyridyloxobutyl cysteine groups were detected by incubating MGMT with ODNs containing the corresponding O6-alkGs. The LOQ of ASPs containing S-methylcysteine detected after MGMT incubation with Me-CT-DNA was <0.05 pmol O6-MeG per mg CT-DNA. Incubation of MGMT with human colorectal DNA produced ASPs containing S-methylcysteine at levels that correlated with those of O6-MeG determined previously by HPLC-radioimmunoassay (r2 = 0.74; p = 0.014). O6-CMG, a putative O6-hydroxyethylG adduct, and other potential unidentified MGMT substrates were also detected in human DNA samples. This novel approach to the identification and quantitation of O6-alkGs in human DNA has revealed the existence of a human DNA alkyl adductome that remains to be fully characterized. The methodology establishes a platform for characterizing the human DNA O6-alkG adductome and, given the mutagenic potential of O6-alkGs, can provide mechanistic information about cancer pathogenesis.

Efficient and flexible estimation of natural direct and indirect effects under intermediate confounding and monotonicity constraints.

Natural direct and indirect effects are mediational estimands that decompose the average treatment effect and describe how outcomes would be affected by contrasting levels of a treatment through changes induced in mediator values (in the case of the indirect effect) or not through induced changes in the mediator values (in the case of the direct effect). Natural direct and indirect effects are not generally point-identified in the presence of a treatment-induced confounder; however, they may be identified if one is willing to assume monotonicity between the treatment and the treatment-induced confounder. We argue that this assumption may be reasonable in the relatively common encouragement-design trial setting, where the intervention is randomized treatment assignment and the treatment-induced confounder is whether or not treatment was actually taken/adhered to. We develop efficiency theory for the natural direct and indirect effects under this monotonicity assumption, and use it to propose a nonparametric, multiply robust estimator. We demonstrate the finite sample properties of this estimator using a simulation study, and apply it to data from the Moving to Opportunity Study to estimate the natural direct and indirect effects of being randomly assigned to receive a Section 8 housing voucher-the most common form of federal housing assistance-on risk developing any mood or externalizing disorder among adolescent boys, possibly operating through various school and community characteristics.

Proton-coupled electron transfer at SOFC electrodes.

Understanding the charge transfer processes at solid oxide fuel cell (SOFC) electrodes is critical to designing more efficient and robust materials. Activation losses at SOFC electrodes have been widely attributed to the ambipolar migration of charges at the mixed ionic-electronic conductor-gas interface. Empirical Butler-Volmer kinetics based on the transition state theory is often used to model the current-voltage relationship, where charged particles transfer classically over an energy barrier. However, the hydrogen oxidation/water electrolysis reaction H2(g) + O2- ⇌ H2O(g) + 2e- must be modeled through concerted electron and proton tunneling events, where we unify the theory of the electrostatic surface potential with proton-coupled electron transfer kinetics. We derive a framework for the reaction rate that depends on the electrostatic surface potential, adsorbate dipole moment, the electronic structure of the electron donor/acceptor, and vibronic states of the hydrogen species. This theory was used to study the current-voltage characteristics of the Ni/gadolinium-doped ceria electrode in H2/H2O(g), where we find excellent validation of this novel model. These results yield the first reported quantification of the solvent reorganization energy for an SOFC material and suggest that the three-phase boundary mechanism is the dominant pathway for charge transfer at cermet electrodes.