INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer.

PURPOSE: Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS). METHODS: A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL). RESULTS: INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports. CONCLUSION: Regorafenib improves survival compared with placebo in refractory AGOC.

Dispersion indices for universal quantification of fluorescently-labelled subcellular structure spatial distributions.

In biology, accurate and robust quantification of biological images is critical for understanding distribution patterns and heterogeneity of subcellular structures within a cell. While various methods tailored to specific biological contexts have been employed for image analysis, there is a need for versatile approaches that transcend the constraints imposed by the intricacies of different biological systems. Here we report the application of dispersion indices - a statistical concept widely used to measure the income distribution within a population by economists - as a powerful and agnostic tool for quantifying biological images, which offers distinct advantages over traditional methods. In our approach, we substitute pixel intensity for income and number of pixels for population. We demonstrate the utility of dispersion indices in quantifying autophagic puncta, mitochondrial clustering, and microtubule dynamics, all of which are key measures relevant for maladies ranging from metabolic and neuronal diseases to cancer. Further, we show utility in 2D cell cultures and a 3D multicellular midbrain culture as well as measurement of a performance metric such as a half maximal effective concentration value (EC50).

Cutibacterium adaptation to life on humans provides a novel biomarker of C. acnes infections.

The domestication of cattle provided Propionibacteriaceae the opportunity to adapt to human skin. These bacteria constitute a distinct genus ( Cutibacterium ), and a single species within that genus ( C. acnes ) dominates 25% of human skin. C. acnes protects humans from pathogen colonization, but it can also infect indwelling medical devices inserted through human skin. Proteins that help Cutibacteria live on our skin may also act as virulence factors during an opportunistic infection, like a shoulder periprosthetic joint infection (PJI). To better understand the evolution of this commensal and opportunistic pathogen, we sought to extensively characterize one of these proteins, RoxP. This secreted protein is only found in the Cutibacterium genus, helps C. acnes grow in oxic environments, and is required for C. acnes to colonize human skin. Structure-based sequence analysis of twenty-one RoxP orthologs (71-100% identity to C. acnes strain KPA171202 RoxP_1) revealed a high-degree of molecular surface conservation and helped identify a potential heme-binding interface. Biophysical evaluation of a subset of seven RoxP orthologs (71-100% identity) demonstrated that heme-binding is conserved. Computational modeling of these orthologs suggests that RoxP heme-binding is mediated by an invariant molecular surface composed of a surface-exposed tryptophan (W66), adjacent cationic pocket, and nearby potential heme axial ligands. Further, these orthologs were found to undergo heme-dependent oligomerization. To further probe the role of this protein in C. acnes biology, we developed four monoclonal anti-RoxP antibodies, assessed the binding of those antibodies to a subset of ten RoxP orthologs (71-100% identity), developed an anti-RoxP sandwich ELISA (sELISA) with sub-nanogram sensitivity, and adapted that sELISA to quantitate RoxP in human biofluids that can be infected by C. acnes (serum, synovial fluid, cerebrospinal fluid). This study expands our understanding of how an environmental bacterium evolved to live on humans, and the assays developed in this work can now be used to identify this organism when it gains access to sterile sites to cause opportunistic infections. Author Summary: The longer humans live, the more they require internal "replacement parts," like prosthetic joints. Increased placement of these and other medical devices has increased their complications, which frequently are infections caused by microbes that live on humans. One of these microbes is Cutibacterium acnes , which dominates 25% of human skin. It appears that when humans domesticated cattle, a C. acnes ancestor adapted from living in cows to living on people. One of these adaptations was RoxP, a protein only found in Cutibacterium and carried by all C. acnes . Here, we describe our extensive characterization of RoxP. We found that distantly related RoxP conserve high stability at the low pH found on human skin. They also conserve the ability to bind heme, a source of iron used by microbes when they infect humans. As a part of this work, we developed tests that measure RoxP to identify C. acnes growth. In a clinic or hospital, these tests could allow a doctor to rapidly identify C. acnes infections, which would improve patient outcomes and lower healthcare costs. This work has helped us better understand how C. acnes adapted to live on humans and to identify C. acnes infections of medical devices.

Criteria for assessing evidence for biomarker-targeted therapies in rare cancers-an extrapolation framework.

Background: Advances in targeted therapy development and tumor sequencing technology are reclassifying cancers into smaller biomarker-defined diseases. Randomized controlled trials (RCTs) are often impractical in rare diseases, leading to calls for single-arm studies to be sufficient to inform clinical practice based on a strong biological rationale. However, without RCTs, favorable outcomes are often attributed to therapy but may be due to a more indolent disease course or other biases. When the clinical benefit of targeted therapy in a common cancer is established in RCTs, this benefit may extend to rarer cancers sharing the same biomarker. However, careful consideration of the appropriateness of extending the existing trial evidence beyond specific cancer types is required. A framework for extrapolating evidence for biomarker-targeted therapies to rare cancers is needed to support transparent decision-making. Objectives: To construct a framework outlining the breadth of criteria essential for extrapolating evidence for a biomarker-targeted therapy generated from RCTs in common cancers to different rare cancers sharing the same biomarker. Design: A series of questions articulating essential criteria for extrapolation. Methods: The framework was developed from the core topics for extrapolation identified from a previous scoping review of methodological guidance. Principles for extrapolation outlined in guidance documents from the European Medicines Agency, the US Food and Drug Administration, and Australia's Medical Services Advisory Committee were incorporated. Results: We propose a framework for assessing key assumptions of similarity of the disease and treatment outcomes between the common and rare cancer for five essential components: prognosis of the biomarker-defined cancer, biomarker test analytical validity, biomarker actionability, treatment efficacy, and safety. Knowledge gaps identified can be used to prioritize future studies. Conclusion: This framework will allow systematic assessment, standardize regulatory, reimbursement and clinical decision-making, and facilitate transparent discussions between key stakeholders in drug assessment for rare biomarker-defined cancers.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3ß-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Immunogenicity and safety of an Entamoeba histolytica adjuvanted protein vaccine candidate (LecA+GLA-3M-052 liposomes) in rhesus macaques.

Entamoeba histolytica, the causative agent of amebiasis, is one of the top three parasitic causes of mortality worldwide. However, no vaccine exists against amebiasis. Using a lead candidate vaccine containing the LecA fragment of Gal-lectin and GLA-3M-052 liposome adjuvant, we immunized rhesus macaques via intranasal or intramuscular routes. The vaccine elicited high-avidity functional humoral responses as seen by the inhibition of amebic attachment to mammalian target cells by plasma and stool antibodies. Importantly, antigen-specific IFN-γ-secreting peripheral blood mononuclear cells (PBMCs) and IgG/IgA memory B cells (BMEM) were detected in immunized animals. Furthermore, antigen-specific antibody and cellular responses were maintained for at least 8 months after the final immunization as observed by robust LecA-specific BMEM as well as IFN-γ+ PBMC responses. Overall, both intranasal and intramuscular immunizations elicited a durable and functional response in systemic and mucosal compartments, which supports advancing the LecA+GLA-3M-052 liposome vaccine candidate to clinical testing.

Retinal vasculopathy with cerebral leukoencephalopathy: a rare mimic of CNS vasculitis.

Retinal vasculopathy with cerebral leukoencephalopathy is a rare autosomal dominant genetic disorder due to mutation in the TREX1 gene and presents with both central nervous system (CNS) and other organ dysfunction. It is often misdiagnosed as demyelination or vasculitis based on imaging features, often with potentially harmful immunotherapy given unnecessarily. This report describes two sisters with progressive hemiparesis, retinal vasculopathy and hepatic dysfunction, one of whom was initially misdiagnosed and treated for cerebral vasculitis. Imaging showed extensive and asymmetric white matter lesions with persistent diffusion restriction and contrast enhancement. Extensive autoimmune and infectious investigations were unremarkable. Both patients had a novel heterozygous variant in the TREX1 gene, giving a diagnosis of retinal vasculopathy with cerebral leukoencephalopathy. Clinicians should consider this condition in atypical presentations of suspected demyelination or CNS vasculitis.

Correcting Edge Defects in Self-Assembled Monolayers through Thermal Annealing.

Self-assembled monolayers (SAMs) are emerging as platform technology for a myriad of applications, yet they still possess varied spatial stability and predictability issues as their properties are heavily dependent on subtle structural features. Reducing entropy within such a system serves as one of many potential solutions to increase order and therefore coherence/precision in measured properties. Here we explore controlled thermal annealing to improve edge disorders in SAMs and significantly reduce data variance. Using both odd- and even-numbered n-alkanethiol SAMs on Au, we observe statistically significant difference in the contact angles between edge and center. Thermal annealing at 40°C significantly narrows differences between edges and centre of the SAM, albeit with significant reduction in the parity dependent odd-even effect. This study provides a pathway to improve SAMs consistency through minimal external perturbation as reflected by the minimization of odd-even effect as SAMs become increasingly ordered.

Scattering approaches to unravel protein solution behaviors in ionic liquids and deep eutectic solvents: From basic principles to recent developments.

Proteins in ionic liquids (ILs) and deep eutectic solvents (DESs) have gained significant attention due to their potential applications in various fields, including biocatalysis, bioseparation, biomolecular delivery, and structural biology. Scattering approaches including dynamic light scattering (DLS) and small-angle X-ray and neutron scattering (SAXS and SANS) have been used to understand the solution behavior of proteins at the nanoscale and microscale. This review provides a thorough exploration of the application of these scattering techniques to elucidate protein properties in ILs and DESs. Specifically, the review begins with the theoretical foundations of the relevant scattering approaches and describes the essential solvent properties of ILs and DESs linked to scattering such as refractive index, scattering length density, ion-pairs, liquid nanostructure, solvent aggregation, and specific ion effects. Next, a detailed introduction is provided on protein properties such as type, concentration, size, flexibility and structure as observed through scattering methodologies. This is followed by a review of the literature on the use of scattering for proteins in ILs and DESs. It is highlighted that enhanced data analysis and modeling tools are necessary for assessing protein flexibility and structure, and for understanding protein hydration, aggregation and specific ion effects. It is also noted that complementary approaches are recommended for comprehensively understanding the behavior of proteins in solution due to the complex interplay of factors, including ion-binding, dynamic hydration, intermolecular interactions, and specific ion effects. Finally, the challenges and potential research directions for this field are proposed, including experimental design, data analysis approaches, and supporting methods to obtain fundamental understandings of complex protein behavior and protein systems in solution. We envisage that this review will support further studies of protein interface science, and in particular studies on solvent and ion effects on proteins.

The chemical assessment of surfaces and air (CASA) study: using chemical and physical perturbations in a test house to investigate indoor processes.

The Chemical Assessment of Surfaces and Air (CASA) study aimed to understand how chemicals transform in the indoor environment using perturbations (e.g., cooking, cleaning) or additions of indoor and outdoor pollutants in a well-controlled test house. Chemical additions ranged from individual compounds (e.g., gaseous ammonia or ozone) to more complex mixtures (e.g., a wildfire smoke proxy and a commercial pesticide). Physical perturbations included varying temperature, ventilation rates, and relative humidity. The objectives for CASA included understanding (i) how outdoor air pollution impacts indoor air chemistry, (ii) how wildfire smoke transports and transforms indoors, (iii) how gases and particles interact with building surfaces, and (iv) how indoor environmental conditions impact indoor chemistry. Further, the combined measurements under unperturbed and experimental conditions enable investigation of mitigation strategies following outdoor and indoor air pollution events. A comprehensive suite of instruments measured different chemical components in the gas, particle, and surface phases throughout the study. We provide an overview of the test house, instrumentation, experimental design, and initial observations - including the role of humidity in controlling the air concentrations of many semi-volatile organic compounds, the potential for ozone to generate indoor nitrogen pentoxide (N2O5), the differences in microbial composition between the test house and other occupied buildings, and the complexity of deposited particles and gases on different indoor surfaces.

Microsecond time-resolved X-ray scattering by utilizing MHz repetition rate at second-generation XFELs.

Detecting microsecond structural perturbations in biomolecules has wide relevance in biology, chemistry and medicine. Here we show how MHz repetition rates at X-ray free-electron lasers can be used to produce microsecond time-series of protein scattering with exceptionally low noise levels of 0.001%. We demonstrate the approach by examining Jɑ helix unfolding of a light-oxygen-voltage photosensory domain. This time-resolved acquisition strategy is easy to implement and widely applicable for direct observation of structural dynamics of many biochemical processes.

Challenges of estimating treatment effects after a positive interim analysis.

BACKGROUND: This research investigates why a beneficial treatment effect reported at the first interim analysis (IA) may diminish at a subsequent analysis (SA). We examined three challenges in interpreting treatment effects from randomized clinical trials (RCTs) after the first positive IA: overestimation bias; non-proportional hazards; and heterogeneity in recruitment. We investigate how a penalized estimation method can address overestimation bias, and discuss additional factors to consider when interpreting positive IA results. METHODS: We identified oncology RCTs reporting positive results at the initial IA and a SA for event-free (EFS) and overall survival (OS). We modeled: (1) the hazard ratio at IA (HRIA) versus its timing as measured by the information fraction (IF; i.e., events at IA versus total events sought); and (2), the ratio of HRIA to HRSA (rHR) versus the IF. This was repeated for HRIA adjusted for overestimation bias. Examples of the other two challenges were sought. RESULTS: Amongst 71 RCTs, HRIA were positively associated with the IF (slope: EFS 0.83, 95 % CI 0.44-1.22; OS 0.25, 95 % CI 0.10-0.41). HRIA tended to exaggerate HRSA, and more so the lower the IF (slope rHR versus IF: EFS 0.10, 95 % CI - 0.22 to 0.42; OS 0.26, 95 % CI 0.07-0.46). Adjusted HRIA did not exaggerate HRSA (slope rHR versus IF: EFS - 0.14, 95 % CI - 0.67 to 0.39; OS 0.02, 95 % CI - 0.26 to 0.30). Examples of two other challenges are shown. CONCLUSION: Overestimation bias, non-proportional hazards, and heterogeneity in recruitment and other important treatments should be considered when communicating estimates of treatment effects from positive IAs.

Theoretical Studies of Anisotropic Melting of Ice Induced by Ultrafast Nonthermal Heating.

Water and ice are routinely studied with X-rays to reveal their diverse structures and anomalous properties. We employ a hybrid collisional-radiative/molecular-dynamics method to explore how femtosecond X-ray pulses interact with hexagonal ice. We find that ice makes a phase transition into a crystalline plasma where its initial structure is maintained up to tens of femtoseconds. The ultrafast melting process occurs anisotropically, where different geometric configurations of the structure melt on different time scales. The transient state and anisotropic melting of crystals can be captured by X-ray diffraction, which impacts any study of crystalline structures probed by femtosecond X-ray lasers.

Crystal structure via fluctuation scattering.

Crystallography is a quintessential method for determining the atomic structure of crystals. The most common implementation of crystallography uses single crystals that must be of sufficient size, typically tens of micrometres or larger, depending on the complexity of the crystal structure. The emergence of serial data-collection methods in crystallography, particularly for time-resolved experiments, opens up opportunities to develop new routes to structure determination for nanocrystals and ensembles of crystals. Fluctuation X-ray scattering is a correlation-based approach for single-particle imaging from ensembles of identical particles, but has yet to be applied to crystal structure determination. Here, an iterative algorithm is presented that recovers crystal structure-factor intensities from fluctuation X-ray scattering correlations. The capabilities of this algorithm are demonstrated by recovering the structure of three small-molecule crystals and a protein crystal from simulated fluctuation X-ray scattering correlations. This method could facilitate the recovery of structure-factor intensities from crystals in serial crystallography experiments and relax sample requirements for crystallography experiments.

The pypadf package: computing the pair angle distribution function from fluctuation scattering data.

The pair angle distribution function (PADF) is a three- and four-atom correlation function that characterizes the local angular structure of disordered materials, particles or nanocrystalline materials. The PADF can be measured using X-ray or electron fluctuation diffraction data, which can be collected by scanning or flowing a structurally disordered sample through a focused beam. It is a natural generalization of established pair distribution methods, which do not provide angular information. The software package pypadf provides tools to calculate the PADF from fluctuation diffraction data. The package includes tools for calculating the intensity correlation function, which is a necessary step in the PADF calculation and also the basis for other fluctuation scattering analysis techniques.

Mechanistic understanding of speciated oxide growth in high entropy alloys.

Complex multi-element alloys are gaining prominence for structural applications, supplementing steels, and superalloys. Understanding the impact of each element on alloy surfaces due to oxidation is vital in maintaining material integrity. This study investigates oxidation mechanisms in these alloys using a model five-element equiatomic CoCrFeNiMn alloy, in a controlled oxygen environment. The oxidation-induced surface changes correlate with each element's interactive tendencies with the environment, guided by thermodynamics. Initial oxidation stages follow atomic size and redox potential, with the latter becoming dominant over time, causing composition inversion. The study employs in-situ atom probe tomography, transmission electron microscopy, and X-ray absorption near-edge structure techniques to elucidate the oxidation process and surface oxide structure evolution. Our findings deconvolute the mechanism for compositional and structural changes in the oxide film and will pave the way for a predictive design of complex alloys with improved resistance to oxidation under extreme conditions.

A healthy breakfast each and every day is important for students' motivation and achievement.

Breakfast is often cited as the most important meal of the day and vital for students' academic functioning at school. Although much research has linked students' breakfast consumption to better achievement, there has been debate about why and how breakfast has academic benefits. The present study of 648 Australian high school students investigated (a) the role of breakfast consumption and breakfast quality in students' self-reported motivation and their achievement in a science test, (b) the role of motivation in mediating the link between breakfast consumption and quality and students' achievement, and (c) the extent to which breakfast consumption effects are moderated by the quality of breakfast (e.g., more vegetables, fruit, dairy/protein, wholegrains, cereals, water; less sugary drinks, processed meat, fast take-away, unhealthy snack foods). Findings indicated that beyond the effects of personal, home, and classroom factors, breakfast consumption predicted higher adaptive motivation (p < .05), breakfast quality predicted lower maladaptive motivation (p < .05), and in turn, students' adaptive (positively, p < .01) and maladaptive (negatively, p < .01) motivation predicted their achievement. Moreover, adaptive motivation significantly mediated the relationship between breakfast consumption and achievement (p < .05). The effect of breakfast consumption was moderated by the quality of breakfast such that consuming a high-quality breakfast in the morning was associated with the highest levels of adaptive motivation (p < .01) and achievement (p < .05) later in the day. Findings have implications for educational practice and policy seeking to promote a healthy start to the school day to optimize students' motivation and achievement.

Improving mentalizing deficits in older age with region-specific transcranial direct current stimulation.

Older adults have difficulties to detect the intentions, thoughts, and feelings of others, indicating an age-associated decline of socio-cognitive abilities that are known as "mentalizing". These deficits in mental state recognition are driven by neurofunctional alterations in brain regions that are implicated in mentalizing, such as the right temporo-parietal junction (rTPJ) and the dorso-medial prefrontal cortex (dmPFC). We tested whether focal transcranial current stimulation (tDCS) of the rTPJ and dmPFC has the potential to eliminate mentalizing deficits in older adults. Mentalizing deficits were assessed with a novel mindreading task that required the recognition of mental states in child faces. Older adults (n = 60) performed worse than younger adults (n = 30) on the mindreading task, indicating age-dependent deficits in mental state recognition. These mentalizing deficits were ameliorated in older adults who received sham-controlled andodal tDCS over the rTPJ (n = 30) but remained unchanged in older adults who received sham-controlled andodal tDCS over the dmPFC (n = 30). We, thus, showed for the first time that anodal tDCS over the rTPJ has the potential to remediate age-dependent mentalizing deficits in a region-specific way. This provides a rationale for exploring stimulation-based interventions targeting mentalizing deficits in older age.