Pulmonary Matrix-derived Hydrogels from Patients with Idiopathic Pulmonary Fibrosis Induce a Proinflammatory State in Lung Fibroblasts In Vitro.

Idiopathic pulmonary fibrosis (IPF), one of the most common forms of interstitial lung disease, is a poorly understood, chronic, and often fatal fibroproliferative condition with only two FDA-approved medications. Understanding the pathobiology of the fibroblast in IPF is critical to evaluating and discovering novel therapeutics. Using a decellularized lung matrix derived from IPF patients, we generate three-dimensional (3D) hydrogels as in vitro models of lung physiology and characterize the phenotype of fibroblasts seeded into the hydrogels. When cultured in IPF ECM hydrogels, IPF fibroblasts display differential contractility compared to their normal counterparts, lose the classical myofibroblast marker α-smooth muscle actin, and increase expression of proinflammatory cytokines compared to fibroblasts seeded two-dimensionally (2D) on tissue culture dishes. We validate this proinflammatory state in fibroblast-conditioned media studies with monocytes and monocyte-derived macrophages. These findings add to a growing understanding of the lung microenvironment effect on fibroblast phenotypes, shed light on the potential role of fibroblasts as immune signaling hubs during lung fibrosis, and suggest intervention in fibroblast-immune cell crosstalk as a possible novel therapeutic avenue.

Preclinical development of a stabilized RH5 virus-like particle vaccine that induces improved antimalarial antibodies.

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage malaria vaccine antigen target, currently in a phase 2b clinical trial as a full-length soluble protein/adjuvant vaccine candidate called RH5.1/Matrix-M. We identify that disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees and that a re-engineered and stabilized immunogen (including just the alpha-helical core of RH5) induces a qualitatively superior growth inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M adjuvant. In parallel, bioconjugation of this immunogen, termed "RH5.2," to hepatitis B surface antigen virus-like particles (VLPs) using the "plug-and-display" SpyTag-SpyCatcher platform technology also enables superior quantitative antibody immunogenicity over soluble protein/adjuvant in vaccinated mice and rats. These studies identify a blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M. The RH5.2-VLP/Matrix-M vaccine candidate is now under evaluation in phase 1a/b clinical trials.

Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex.

Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.

Food insecurity and periodontitis in US adults.

OBJECTIVES: To determine the relationship between food insecurity and periodontitis among adults in the United States (US). METHODS: Secondary analysis of the 2009-2014 National Health and Nutrition Examination Survey data. The sample included 6,108 US participants aged ≥ 30 years in a probability weighted sample. Periodontitis status was measured in full-month oral examinations at 6 sites per tooth for clinical attachment loss and periodontal probing depth. Food insecurity was assessed by the 18-item US Food Security Survey Module. RESULTS: Controlling for covariates, multiple logistic regression showed that periodontitis was associated with low food security (adjusted odds ratio (aOR)=1.30, 95% CI: 1.08-1.57). Risk factors for periodontitis included HbA1c ≥ 7% (aOR=1.74, 95% CI: 1.26-2.40), seeking emergency dental care (aOR=1.36, 95% CI:1.19-1.55), smoking status, racial minorities, low income, and older age. Protective factors for periodontitis were annual dental visit (aOR=0.52, 95% CI: 0.43-0.64), health insurance (aOR=0.66, 95% CI: 0.54-0.80), female gender, and college education. CONCLUSIONS: Food insecurity was associated with a higher risk of periodontitis among US adults. Having enough food to eat is a basic human right and would improve well-being.

Do measures of social support and social distress share general factors associated with suicidal ideation and attempts?

INTRODUCTION: Aspects of social relationships have variably been associated with suicidal ideation (SI) and suicide attempts (SAs). This study assessed whether social support and social distress measures have general factors versus measure-specific factors that are associated with suicide risk. METHODS: Adults (N = 455, 60.0% female), admitted to psychiatric inpatient units following a recent suicide attempt or active SI, completed assessments of social support (emotional support, instrumental support, friendship, perceived support from significant others, friends, family) and social distress (loneliness, perceived rejection, perceived burdensomeness, thwarted belongingness). Bifactor modeling examined general and specific factors of social support and distress in relation to SI (week prior to hospitalization, via the Beck Scale for SI) and SAs (past 30 days, via the Columbia Suicide Severity Rating Scale). RESULTS: SI was significantly associated with the general social support (B = -1.51), the general social distress (B = 1.67), and the specific perceived burdensomeness (B = 1.57) factors. SAs were significantly associated with the specific Perceived Rejection (OR = 1.05) and Thwarted Belongingness (OR = 0.91) factors. CONCLUSION: General social support and social distress were associated with SI but not recent SAs. Specific social distress factors were also related to SI and SAs controlling for general social distress, suggesting areas for future interventions.

Establishing RTS,S/AS01 as a benchmark for comparison to next-generation malaria vaccines in a mouse model.

New strategies are needed to reduce the incidence of malaria, and promising approaches include vaccines targeting the circumsporozoite protein (CSP). To improve upon the malaria vaccine, RTS,S/AS01, it is essential to standardize preclinical assays to measure the potency of next-generation vaccines against this benchmark. We focus on RTS,S/AS01-induced antibody responses and functional activity in conjunction with robust statistical analyses. Transgenic Plasmodium berghei sporozoites containing full-length P. falciparum CSP (tgPb-PfCSP) allow two assessments of efficacy: quantitative reduction in liver infection following intravenous challenge, and sterile protection from mosquito bite challenge. Two or three doses of RTS,S/AS01 were given intramuscularly at 3-week intervals, with challenge 2-weeks after the last vaccination. Minimal inter- and intra-assay variability indicates the reproducibility of the methods. Importantly, the range of this model is suitable for screening more potent vaccines. Levels of induced anti-CSP antibody 2A10 equivalency were also associated with activity: 105 µg/mL (95% CI: 68.8, 141) reduced liver infection by 50%, whereas 285 µg/mL (95% CI: 166, 404) is required for 50% sterile protection from mosquito bite challenge. Additionally, the liver burden model was able to differentiate between protected and non-protected human plasma samples from a controlled human malaria infection study, supporting these models' relevance and predictive capability. Comparison in animal models of CSP-based vaccine candidates to RTS,S/AS01 is now possible under well controlled conditions. Assessment of the quality of induced antibodies, likely a determinant of durability of protection in humans, should be possible using these methods.

A candidate antibody drug for prevention of malaria.

Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO's preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross stage recognition of glutamate-rich repeats.

Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies (Abs) can efficiently block parasite transmission. In search for naturally acquired Ab targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gamete and gametocyte extract. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for PfCSP, extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf . Impact Statement: A naturally acquired human monoclonal antibody recognizes proteins expressed at different stages of the Plasmodium falciparum lifecycle through affinity-matured homotypic interactions with glutamate-rich repeats.

Pfs230 Domain 7 is targeted by a potent malaria transmission-blocking monoclonal antibody.

Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that block Plasmodium parasite development in the mosquito midgut, thus preventing mosquitoes from becoming infectious. While the Pro-domain and first of fourteen 6-Cysteine domains (Pro-D1) of the Plasmodium gamete surface protein Pfs230 are known targets of transmission-blocking antibodies, no studies to date have discovered other Pfs230 domains that are functional targets. Here, we show that a murine monoclonal antibody (mAb), 18F25.1, targets Pfs230 Domain 7. We generated a subclass-switched complement-fixing variant, mAb 18F25.2a, using a CRISPR/Cas9-based hybridoma engineering method. This subclass-switched mAb 18F25.2a induced lysis of female gametes in vitro. Importantly, mAb 18F25.2a potently reduced P. falciparum infection of Anopheles stephensi mosquitoes in a complement-dependent manner, as assessed by standard membrane feeding assays. Together, our data identify Pfs230 Domain 7 as target for transmission-blocking antibodies and provide a strong incentive to study domains outside Pfs230Pro-D1 as TBV candidates.

A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment.

All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA's anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA's anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice-a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.

Denoising task-related fMRI: Balancing noise reduction against signal loss.

Preprocessing fMRI data requires striking a fine balance between conserving signals of interest and removing noise. Typical steps of preprocessing include motion correction, slice timing correction, spatial smoothing, and high-pass filtering. However, these standard steps do not remove many sources of noise. Thus, noise-reduction techniques, for example, CompCor, FIX, and ICA-AROMA have been developed to further improve the ability to draw meaningful conclusions from the data. The ability of these techniques to minimize noise while conserving signals of interest has been tested almost exclusively in resting-state fMRI and, only rarely, in task-related fMRI. Application of noise-reduction techniques to task-related fMRI is particularly important given that such procedures have been shown to reduce false positive rates. Little remains known about the impact of these techniques on the retention of signal in tasks that may be associated with systemic physiological changes. In this paper, we compared two ICA-based, that is FIX and ICA-AROMA, two CompCor-based noise-reduction techniques, that is aCompCor, and tCompCor, and standard preprocessing using a large (n = 101) fMRI dataset including noxious heat and non-noxious auditory stimulation. Results show that preprocessing using FIX performs optimally for data obtained using noxious heat, conserving more signals than CompCor-based techniques and ICA-AROMA, while removing only slightly less noise. Similarly, for data obtained during non-noxious auditory stimulation, FIX noise-reduction technique before analysis with a covariate of interest outperforms the other techniques. These results indicate that FIX might be the most appropriate technique to achieve the balance between conserving signals of interest and removing noise during task-related fMRI.

FEEDING PRACTICES AND NUTRITIONAL STATUS OF UNDER-FIVE CHILDREN IN A PERI-URBAN SETTING IN IBADAN, SOUTHWEST NIGERIA: A COMPARATIVE CROSS-SECTIONAL STUDY.

Background: Existing literature suggests inequalities in nutritional and feeding practices for children in rural communities compared to their urban counterparts. However, with increasing urbanization and changing social norms, re-assessment of rural-urban differences in feeding practices for under-five children is essential. This study therefore aimed to assess the feeding practices and nutritional status of children in a peri-urban setting in Ibadan. Methods: We conducted a community-based cross-sectional comparative study in peri-urban LGA (Lagelu) in Ibadan. Participants were 617 caregivers of underfive children identified, from wards typical of rural and urban settings, through a multistage sampling technique. Caregivers' sociodemographic details, 24-hour dietary recall of the child's feeding, and anthropometric measurements were obtained. Results: Nearly half of the children were 2 years or older (rural: n=142, 47.2%; urban: n=147, 46.2%). There was significant difference between settings in terms of maternal age and education, father's education, caregiver's occupation and socioeconomic status. In total, 611 children (99.0%) were breastfed. Of those breastfed, 45% and 39% in rural and urban settings respectively were initiated within an hour of delivery. Children in rural setting had longer duration of breast feeding. However, they are less likely to be exclusively breast fed for 6 - months compared with children whose caregivers are urban dwellers. Dietary diversity was similar in both settings but higher among males. (20.3% male, 11.7% female in rural; 17.3% male and 15.5% female in urban). Overall, 108 (22.3%), 107 (21.9%), 152 (30.6%) and 34 (7.0%) of children aged 6-59 months were cachetic, underweight, stunted, and overweight respectively but commoner among children in rural settings. Conclusion: Feeding and nutrition programmes need to apply a gender lens if sustained behavioural interventions on child nutrition are to reach equitable outcomes.

Size-dependent diffusion of supported metal nanoclusters: mean-field-type treatments and beyond for faceted clusters.

Nanostructured systems are intrinsically metastable and subject to coarsening. For supported 3D metal nanoclusters (NCs), coarsening can involve NC diffusion across the support and subsequent coalescence (as an alternative to Ostwald ripening). When used as catalysts, this leads to deactivation. The dependence of diffusivity, DN, on NC size, N (in atoms), controls coarsening kinetics. Traditional mean-field (MF) theory for DNversus N assumes that NC diffusion is mediated by independent random hopping of surface adatoms with low coordination, and predicts that DN ∼ hN-4/3neq. Here, h = ν exp[-Ed/(kBT)] denotes the hop rate, and neq = exp[-Eform/(kBT)] the density of those adatoms. The adatom formation energy, Eform, approaches a finite large-N limit, as does the effective barrier, Eeff = Ed + Eform, for NC diffusion. This MF theory is critically assessed for a realistic stochastic atomistic model for diffusion of faceted fcc metal NCs with a {100} facet epitaxially attached to a (100) support surface. First, the MF formulation is refined to account for distinct densities and hop rates for surface adatoms on different facets and along the base contact line, and to incorporate the exact values of Eform and neqversus N for our model. MF theory then captures the occurrence of local minima in DNversus N at closed-shell sizes, as shown by KMC simulation. However, the MF treatment also displays fundamental shortcomings due to the feature that diffusion of faceted NCs is actually dominated by a cooperative multi-step process involving disassembling and reforming of outer layers on side facets. This mechanism leads to an Eeff which is well above MF values, and which increases with N, features captured by a beyond-MF treatment.

ß-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify ß-hydroxybutyrate (ßHB), a ketone body, as a regulator of protein solubility in the aging brain. ßHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate ßHB-induced protein insolubility across in vitro, ex vivo, and in vivo mouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-ß, and exogenous ßHB ameliorates pathology in nematode models of amyloid-ß aggregation toxicity. We have generated a comprehensive atlas of the ßHB-induced protein insolublome ex vivo and in vivo using mass spectrometry proteomics, and have identified common protein domains within ßHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among ßHB targets and the clearance of these targets from mouse brain, likely via ßHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.

Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.

The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.

Nucleation-mediated reshaping of facetted metallic nanocrystals: Breakdown of the classical free energy picture.

Shape stability is key to avoiding degradation of performance for metallic nanocrystals synthesized with facetted non-equilibrium shapes to optimize properties for catalysis, plasmonics, and so on. Reshaping of facetted nanocrystals is controlled by the surface diffusion-mediated nucleation and growth of new outer layers of atoms. Kinetic Monte Carlo (KMC) simulation of a realistic stochastic atomistic-level model is applied to precisely track the reshaping of Pd octahedra and nanocubes. Unexpectedly, separate constrained equilibrium Monte Carlo analysis of the free energy profile during reshaping reveals a fundamental failure of the classical nucleation theory (CNT) prediction for the reshaping barrier and rate. Why? Nucleation barriers can be relatively low for these processes, so the system is not locally equilibrated before crossing the barrier, as assumed in CNT. This claim is supported by an analysis of a first-passage problem for reshaping within a master equation framework for the model that reasonably captures the behavior in KMC simulations.

Highly potent, naturally acquired human monoclonal antibodies against Pfs48/45 block Plasmodium falciparum transmission to mosquitoes.

Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite development in the mosquito, thereby blocking onward transmission, and provide a much-needed tool for malaria control and elimination. The parasite surface protein Pfs48/45 is a leading TBV candidate. Here, we isolated and characterized a panel of 81 human Pfs48/45-specific monoclonal antibodies (mAbs) from donors naturally exposed to Plasmodium parasites. Genetically diverse mAbs against each of the three domains (D1-D3) of Pfs48/45 were identified. The most potent mAbs targeted D1 and D3 and achieved >80% transmission-reducing activity in standard membrane-feeding assays, at 10 and 2 µg/mL, respectively. Co-crystal structures of D3 in complex with four different mAbs delineated two conserved protective epitopes. Altogether, these Pfs48/45-specific human mAbs provide important insight into protective and non-protective epitopes that can further our understanding of transmission and inform the design of refined malaria transmission-blocking vaccine candidates.

Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230.

Pfs230 is essential for Plasmodium falciparum transmission to mosquitoes and is the protein targeted by the most advanced malaria-transmission-blocking vaccine candidate. Prior understanding of functional epitopes on Pfs230 is based on two monoclonal antibodies (mAbs) with moderate transmission-reducing activity (TRA), elicited from subunit immunization. Here, we screened the B cell repertoire of two naturally exposed individuals possessing serum TRA and identified five potent mAbs from sixteen Pfs230 domain-1-specific mAbs. Structures of three potent and three low-activity antibodies bound to Pfs230 domain 1 revealed four distinct epitopes. Highly potent mAbs from natural infection recognized a common conformational epitope that is highly conserved across P. falciparum field isolates, while antibodies with negligible TRA derived from natural infection or immunization recognized three distinct sites. Our study provides molecular blueprints describing P. falciparum TRA, informed by contrasting potent and non-functional epitopes elicited by natural exposure and vaccination.

Predicting short-term suicidal thoughts in adolescents using machine learning: developing decision tools to identify daily level risk after hospitalization.

BACKGROUND: Mobile technology offers unique opportunities for monitoring short-term suicide risk in daily life. In this study of suicidal adolescent inpatients, theoretically informed risk factors were assessed daily following discharge to predict near-term suicidal ideation and inform decision algorithms for identifying elevations in daily level risk, with implications for real-time suicide-focused interventions. METHODS: Adolescents (N = 78; 67.9% female) completed brief surveys texted daily for 4 weeks after discharge (n = 1621 observations). Using multi-level classification and regression trees (CARTSs) with repeated 5-fold cross-validation, we tested (a) a simple prediction model incorporating previous-day scores for each of 10 risk factors, and (b) a more complex model incorporating, for each of these factors, a time-varying person-specific mean over prior days together with deviation from that mean. Models also incorporated missingness and contextual (study week, day of the week) indicators. The outcome was the presence/absence of next-day suicidal ideation. RESULTS: The best-performing model (cross-validated AUC = 0.86) was a complex model that included ideation duration, hopelessness, burdensomeness, and self-efficacy to refrain from suicidal action. An equivalent model that excluded ideation duration had acceptable overall performance (cross-validated AUC = 0.78). Models incorporating only previous-day scores, with and without ideation duration (cross-validated AUC of 0.82 and 0.75, respectively), showed relatively weaker performance. CONCLUSIONS: Results suggest that specific combinations of dynamic risk factors assessed in adolescents' daily life have promising utility in predicting next-day suicidal thoughts. Findings represent an important step in the development of decision tools identifying short-term risk as well as guiding timely interventions sensitive to proximal elevations in suicide risk in daily life.