Large Effect Research Articles

MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy

Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction= 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction= 0.01; PTEN P interaction= 0.002). The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Structure-Photoreactivity Studies of BODIPY Photocages: Limitations of the Activation Barrier for Optimizing Photoreactions.

BODIPY photocages are photoreactive chromophores that release covalently linked cargo upon absorption of visible light. Here, we used computations of the T1 photoheterolysis barrier to ascertain whether a computational approach could assist in a priori structure design by identifying new structures with higher quantum yields of photorelease. The electronic structure-photoreactivity relationships were elucidated for boron-substituted and core-functionalized 2-substituted BODIPY photocages as well as aryl substitutions at the meso-methyl position. Although there is a clear trend for the 2-substituted derivatives, with donor-substituted derivatives featuring both lower computed barriers and higher experimental quantum yields, no trend in the quantum yield with the computed activation barrier is found for the meso-methyl-substituted or boron-substituted derivatives. The lack of a correlation between the experimental quantum yield with the computed barrier in the latter two substitution cases is attributed to the substituents having larger effects on the rates of competing channels (internal conversion and competitive photoreactions) than on the rate of the photoheterolysis channel. Thus, although in some cases computed photoreaction barriers can aid in identifying structures with higher quantum yields, the ignored impacts of how changing the structure affects the rates of competing photophysical/photochemical channels limit the effectiveness of this single-parameter approach.

Abstract PO4-03-11: Discerning the impact of ctDNA detection on patient decisions in early-stage breast cancer

Abstract Background: Detection of circulating tumor DNA (ctDNA) after neoadjuvant therapy for triple negative breast cancer (TNBC) is associated with increased risk of recurrence. Ongoing trials aim to determine whether knowledge of specific genomic mutations in ctDNA can inform targeted adjuvant therapy to improve prognosis. The impact of knowledge of ctDNA status on patient treatment decisions weighing benefit and toxicity is unknown. Methods: 401 women were recruited via the Research Advocacy Network from Young Survivors’ Coalition, Living Beyond Breast Cancer, and Pink-4-Ever Ending Disparities. Participants had to self-report a history of non-metastatic breast cancer and have received chemotherapy in the prior 6 months to 10 years to be eligible. Participants completed a 27 question Qualtrics survey detailing demographics and experience with prior chemotherapy. Based on estimations from prior data, participants were presented with scenarios mimicking residual TNBC and unknown, negative, or positive ctDNA status with corresponding risk of recurrence of 40%, 20%, or 55% respectively. Participants were then presented with 12 scenarios (in random order) combining various degrees of absolute risk reduction (5%, 15%, 35%) with established toxicity profiles of four possible post-neoadjuvant therapies (capecitabine, immunotherapy, PARP inhibitor, and PI3K inhibitor). Participants rated scenarios in terms of acceptability from 0-100. A general linear model with repeated measures (3 × 4) was used to determine the contributions of risk reduction and toxicity to acceptability. Models were also run with the addition of between subject factors: age group (< 40; >40), stage of cancer (Stage 1; Stage 2/3), and previous experience with toxicity (Yes; No), to examine whether any of these factors moderated the effects of risk reduction and toxicity. Effect sizes were determined by partial h2. Results: 286 eligible respondents completed the survey with evaluable responses. Average age was 41.2 (range 27-75). When the hypothetical risk of recurrence decreased from 40% (ctDNA-unknown) to 20% (ctDNA-negative), significantly less participants preferred adjuvant capecitabine vs. no therapy (95.1% versus 63.3%, p< 0.001). Across the 12 scenarios, both benefit (F=448.5, p< 0.001; preference for greater benefit) and toxicity (F=33.64, p< 0.001; preference for lower toxicity) significantly influenced acceptability, but benefit had a much larger effect size than toxicity (h2=0.76 and 0.26, respectively). There was no significant interaction effect, and the pattern of results was not moderated by age, stage of cancer, or prior experience with chemotherapy toxicity. The most preferred scenario (greatest benefit, lowest toxicity) had a mean rating of 87.8/100; however, even when presented with the scenario with the lowest benefit and highest toxicity, the mean rating was still 31.5/100, suggesting that this combination would be acceptable to some individuals. Conclusions: Knowledge of ctDNA-negative status significantly reduced the number of participants preferring adjuvant capecitabine over no further therapy. When faced with ctDNA-positive status, participants preferred maximum risk reduction regardless of toxicity profile. As genomic technology advances, it is imperative that researchers and treating physicians understand its impact on patient decision making. Citation Format: Tarah Ballinger, Gregory Zimet, Elda Railey, Mary Lou Smith, Bryan Schneider. Discerning the impact of ctDNA detection on patient decisions in early-stage breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-11.

Effect of an herbivorous subterranean rodent on vegetation in relation to primary productivity

AbstractSubterranean rodents modify the surrounding environment being classified, in some cases, as keystone species and/or ecosystem engineers. This role could be context‐dependent if the changes produced shift throughout the species distribution range and are stronger under certain environmental conditions. Our objective was to analyse whether the effect of Ctenomys mendocinus on vegetation cover is context‐dependent. Given that primary productivity may increase plants' ability to tolerate or compensate following herbivory, we hypothesize that the effect of C. mendocinus on vegetation cover will be context‐dependent along a primary productivity gradient, with smaller effects in highly productive environments and larger effects in less productive ones. We compared the effect of C. mendocinus on plant cover among four contrasting environments and found that it depended on primary productivity in a predictable manner. In low productivity environments, the rodent significantly reduces vegetation cover, while it has no discernible effect in highly productive ones. These findings suggest that the effect of C. mendocinus on plant cover depends on primary productivity level and highlights the importance of accounting for the underlying environmental factors that influence the intensity of C. mendocinus–plant interaction.

From aid to resilience: Assessing the impact of climate finance on energy vulnerability in developing countries

Climate change is a major threat, and tackling it requires massive investment in sustainable practices and technologies. This paper explores the impact of the Global Climate Finance Fund (CF), including the Adaptation Finance Fund (AF) and Mitigation Finance Fund (MF), on energy vulnerability from 2000 to 2019 in a panel of 74 developing countries. Estimation using the Ordinary Least Squares (OLS) method showed that the CF significantly reduces energy vulnerability in developing countries. Furthermore, these results show that the MF has a greater reduction effect on energy vulnerability than the AF. To deal with the omitted variables bias and reverse causality, we applied the Oster (2019) stability test, and the Instrumental Variable Generalized Method of Moments (IV-GMM). The results confirm previous findings that climate finance reduces energy vulnerability, with mitigation finance having a larger effect. These results remained robust to the introduction of additional controls, to the exclusion of outliers, and to the use of alternative climate finance measures. Instrumenting climate finance by the share of important votes at the UN General Assembly and using three different instrumental estimation techniques, such as the Instrumental Variable Two-Stage Least Squares (IV-2SLS), Lewbel (2012), and Kiviet (2020), does not change our results. Finally, an asymmetry analysis through the application of the Canay (2011) quantile regression demonstrated that climate finance reduces energy vulnerability only for countries with a medium and high level of energy vulnerability. Based on these results, policy recommendations have been formulated.

Using tensile and compressive stress superposition during incremental forming to manipulate martensitic transformation in SS304

Single point incremental forming (SPIF) is a flexible manufacturing process that has applications in industries ranging from biomedical to automotive. In addition to rapid prototyping, which requires easy adaptations in geometry or material for design changes, control of the final part properties is desired. One strategy that can be implemented is stress superposition, which is the application of additional stresses during an existing manufacturing process. Tensile and compressive stresses applied during SPIF showed significant effects on the resulting microstructure in stainless steel 304 truncated square pyramids. Specifically, the amount of martensitic transformation was increased through stress superposed incremental forming. Finite element analyses with advanced material modeling supported that the stress triaxiality had a larger effect than the Lode angle parameter on the phase transformation that occurred during deformation. By controlling the amount of tensile and compressive stresses superposed during incremental forming, the microstructure of the final component can be manipulated based on the intended application and desired final part properties.

Effect-Size Discrepancies in Literature Versus Raw Datasets from Experimental Spinal Cord Injury Studies: A CLIMBER Meta-Analysis.

Translation of spinal cord injury (SCI) therapeutics from pre-clinical animal studies into human studies is challenged by effect size variability, irreproducibility, and misalignment of evidence used by pre-clinical versus clinical literature. Clinical literature values reproducibility, with the highest grade evidence (class 1) consisting of meta-analysis demonstrating large therapeutic efficacy replicating across multiple studies. Conversely, pre-clinical literature values novelty over replication and lacks rigorous meta-analyses to assess reproducibility of effect sizes across multiple articles. Here, we applied modified clinical meta-analysis methods to pre-clinical studies, comparing effect sizes extracted from published literature to raw data on individual animals from these same studies. Literature-extracted data (LED) from numerical and graphical outcomes reported in publications were compared with individual animal data (IAD) deposited in a federally supported repository of SCI data. The animal groups from the IAD were matched with the same cohorts in the LED for a direct comparison. We applied random-effects meta-analysis to evaluate predictors of neuroconversion in LED versus IAD. We included publications with common injury models (contusive injuries) and standardized end-points (open field assessments). The extraction of data from 25 published articles yielded n = 1841 subjects, whereas IAD from these same articles included n = 2441 subjects. We observed differences in the number of experimental groups and animals per group, insufficient reporting of dropout animals, and missing information on experimental details. Meta-analysis revealed differences in effect sizes across LED versus IAD stratifications, for instance, severe injuries had the largest effect size in LED (standardized mean difference [SMD = 4.92]), but mild injuries had the largest effect size in IAD (SMD = 6.06). Publications with smaller sample sizes yielded larger effect sizes, while studies with larger sample sizes had smaller effects. The results demonstrate the feasibility of combining IAD analysis with traditional LED meta-analysis to assess effect size reproducibility in SCI.

Treating benign paroxysmal positional vertigo in acute traumatic brain injury: a prospective, randomised clinical trial assessing safety, feasibility, and efficacy

BackgroundBenign paroxysmal positional vertigo (BPPV) affects approximately half of acute, moderate-severe traumatic brain injury (TBI) patients. To date, there have been no rigorous studies of BPPV assessment or treatment in...

Material Characterization Augmented with Artificial Intelligence.

The present paper investigates the application of artificial intelligence to improve the results from simple, non-instrumented, tensile tests, performed with a desktop-size MaCh3D smart universal testing machine. Non-instrumented tensile tests, performed on any testing machine, are affected by both deterministic and random factors that introduce errors in the test results. Specific features of the MaChh3D tester minimize random factors effects on test results while introducing a larger effect of deterministic factors. Artificial intelligence is identified as a novel approach to correct errors in non-instrumented tensile test, capable of simulating a direct strain measure onto the test, replacing traditional contact or non-contact instrumentations (like strain-gages, extensometer and optical measures) that introduce complexity into test procedure and require time for setup. The resulting AI model implementation is described and its performance evaluated in comparison with instrumented tests, also comparing different training strategies. The developed AI-extensometer (artificial intelligence virtual extensometer), is capable of a precise mechanical properties evaluation, with errors from 0 to 10% depending on the specific parameter.

Teaching Adolescents about Stress Using a Universal School-Based Psychoeducation Program: A Cluster Randomised Controlled Trial

Psychoeducation programs may increase knowledge about stress and help adolescents cope with stress. However, research about the effectiveness of psychoeducation programs about stress for adolescents is limited. The present study aimed to fill this gap by evaluating the effect of a brief school-based universal psychoeducation program about stress, the Stress Lessons, in terms of knowledge and experienced stress. A total of 1613 adolescents (M = 13.41 years) from Dutch secondary schools participated. A cluster randomised controlled design was employed: classes were randomly assigned to an experimental or control condition. The experimental condition received three Stress Lessons between pre- and post-test. The Stress Lessons provided information about stress, how to recognize stress, and how to cope with and prevent stress. Questionnaires were used to assess knowledge about stress as well as experienced stress. Multilevel analyses were conducted to examine the effectiveness of the Stress Lessons and the moderating effect of gender, educational track, and ethnic background. Results showed that knowledge gain was significantly greater in the experimental than in the control condition. Experienced stress did not change due to the Stress Lessons. Moderator analyses revealed a larger effect of the Stress lessons in terms of knowledge about stress for girls compared to boys and for adolescents who followed academic compared to vocational education. Overall, the findings show that a brief psychoeducation program leads to a better understanding of stress. Therefore, it may be useful for schools to implement such programs to enhance adolescents’ awareness.

CPPS and Voice-Source Parameters: Objective Analysis of the Singing Voice.

In recent years cepstral analysis and specific cepstrum-based measures such as smoothed cepstral peak prominence (CPPS) has become increasingly researched and utilized in attempts to determine the extent of overall dysphonia in voice signals. Yet, few studies have extensively examined how specific voice-source parameters affect CPPS values. Using a range of synthesized tones, this exploratory study sought to systematically analyze the effect of fundamental frequency (fo), vibrato extent, source-spectrum tilt, and the amplitude of the voice-source fundamental on CPPS values. A series of scales were synthesised using the freeware Madde. Fundamental frequency, vibrato extent, source-spectrum tilt, and the amplitude of the voice-source fundamental were systematically and independently varied. The tones were analysed in PRAAT, and statistical analyses were conducted in SPSS. CPPS was significantly affected by both fo and source-spectrum tilt, independently. A nonlinear association was seen between vibrato extent and CPPS, where CPPS values increased from 0 to 0.6 semitones (ST), then rapidly decreased approaching 1.0 ST. No relationship was seen between the amplitude of the voice-source fundamental and CPPS. The large effect of fo should be taken into account when analyzing the voice, particularly in singing-voice research, when comparing pre and posttreatment data, and when comparing inter-subject CPPS data.

Expanding access to identification cards and social programs: Experimental evidence from Panamá

AbstractWe experimentally analyze the effects of an intervention to induce the renewal of identification cards on access to a government social program in Panamá. On‐time renewals and access to government transfers increased by 10 and 3.6 percentage points, respectively. Simple reminders about expiration dates generated larger effects than also enabling individuals to renew their documents through an online platform, which users struggled to use despite its being designed to simplify the process. The results suggest that increasing access to identity documentation can reduce exclusion errors in social programs and that simply granting access to e‐government platforms may not necessarily improve public service delivery.

Automatic price appraisals: why they matter and how to measure them.

Accurately estimating consumers' willingness-to-pay (WTP) is crucial to product design, pricing decisions, and the design of competitive marketing strategies. However, traditional self-report measures of WTP are susceptible to many reporting biases, including tactical responding or an inability to make accurate estimates. Importantly, appraisals also occur automatically (i.e., in the absence of substantial time, intention, awareness, and/or substantial cognitive resources) and implicit measures used to capture automatic appraisals are less susceptible to the sort of reporting biases that self-report measures can be affected by. However, the only existing implicit measure for assessing automatic price appraisals (the Task Rule Congruency paradigm, 'TRC') is impractical because of the large number of trials and time it requires. Accordingly, here we introduce the Implicit Attribute Classification Task (IMPACT), test its effectiveness for the measurement of automatic price appraisals (Study 1), and directly compare its effectiveness and utility with that of the TRC (Study 2). We find that the IMPACT is an efficient measure of automatic price appraisals, that it produces considerably larger effects compared to the TRC, and that it does so while substantially shortening the procedure. We also discuss how the IMPACT scores can be used to derive an implicit measure of willingness to pay. Our findings make a substantial contribution to both research and practice by providing an effective tool that facilitates, for the first time, an efficient exploration of implicit WTP.

Water status dynamics and drought tolerance of juvenile European beech, Douglas fir and Norway spruce trees as dependent on neighborhood and nitrogen supply.

To increase the resilience of forests to drought and other hazards, foresters are increasingly planting mixed stands. This requires knowledge about the drought response of tree species in pure and mixed-culture neighborhoods. In addition, drought frequently interacts with continued atmospheric nitrogen (N) deposition. To disentangle these factors for European beech, Norway spruce and Douglas fir, we conducted a replicated 3-factorial sapling growth experiment with three moisture levels, (high, medium, and low), two N levels (high and ambient), and pure and mixed-culture neighborhoods. We measured biomass, stomatal conductance (GS), shoot water potential (at predawn: ΨPD, midday, and turgor loss point: ΨTLP), branch xylem embolism resistance (Ψ50) and minimum epidermal conductance (Gmin). The three species differed most with respect to Gmin (10-fold higher in beech than in the conifers), hydroscape area (larger in beech), and the time elapsed to reach stomatal closure (TΨGS90) and ΨTLP (TTLP; shorter in beech), while Ψ50 and ΨTLP were remarkably similar. Neighborhood (pure vs mixed-culture) influenced biomass production, water status and hydraulic traits, notably GS (higher in Douglas fir, but lower in spruce and beech, in mixtures than pure culture), hydraulic safety margin (smaller for beech in mixtures), and TΨGS90 and TTLP (shorter for spruce in mixture). High N generally increased GS, but no consistent N effects on leaf water status and hydraulic traits were detected, suggesting that neighbor identity had a larger effect on plant water relations than N availability. We conclude that both tree neighborhood and N availability modulate the drought response of beech, spruce, and Douglas fir. Species mixing can alleviate the drought stress of some species, but often by disadvantaging other species. Thus, our study suggests that stabilizing and building resilience of production forests against a drier and warmer climate may depend primarily on the right species choice; species mixing can support the agenda.

Cross-linguistic effects of form overlap in aural recognition of Spanish–English cognates

Abstract This study investigated the effect of cross-linguistic overlap in L1 and L2 auditory recognition of Spanish–English cognates. The study examined the correlation between objective and subjective measures of overlap and analyzed how these measures predict patterns in auditory recognition. 62 Spanish-speaking learners of English and 63 English-speaking learners of Spanish completed two auditory lexical decision tasks in Spanish and English and a rating task, where they rated the perceived phonological similarity of cognates. The results revealed moderate correlations between subjective and objective measures of overlap. While orthographic overlap had no effect, increased phonological overlap facilitated recognition in L1 and L2 Spanish and English and had larger effects in L2 recognition. Perceived similarity was the best predictor among the measures of overlap. The findings support models suggesting that cross-linguistic co-activation is facilitated by increased form similarity and studies reporting modality dependent effects of cross-linguistic form overlap in lexical recognition.

The potential of following-up international large-scale assessment studies: using PISA 2018 to develop a comprehensive model of effective teaching

ABSTRACT The paper investigates the potential of using international large-scale assessment studies for conducting follow-up studies testing models of educational effectiveness. The impact of teacher factors coming from the dynamic model of educational effectiveness and the dialogic education theory on student literacy achievement is examined. Modern Greek teachers from secondary schools that participated in PISA 2018 (Accessed on https://www.oecd.org/pisa/data/pisa2018technicalreport/) in Cyprus were recruited. Two Grade 11 classes per teacher were selected, giving 392 students in total. Observation data from Greek lessons and student literacy achievement data were collected. Two multilevel regression analyses were conducted: one with the whole student sample and one with only students from whom PISA prior achievement measure was identified. When prior achievement (i.e., PISA measure) was considered, additional and larger effects of factors on student final achievement were detected. Both analyses reveal that when factors from both frameworks were considered, larger variance in student achievement was explained.

The role of possession of durable goods in gender-based developmentally-situated educational disparities in Colombia

There is growing recognition that anti-poverty policies aimed at increasing access to assets, particularly durable goods, need to address the issue of gender-based developmentally-situated disparities. This study examined how different types of durable goods relate to academic achievement and school attendance in Colombia and whether this relationship varies by gender and school grade, expanding the geographic scope of existing literature on the subject to Latin America. Data for fifth and ninth-grade students with complete durable goods information (N = 364,436) from the 2017 SABER test, a nationwide examination that evaluates reading and math skills, were assessed using multilevel modeling. The results indicated that students whose families owned washing machines, computers or who had internet access performed better academically and were less likely to be absent from school, with larger effects for boys and fifth graders. This research contributes to the existing literature by illustrating the importance of durable goods on children's academic performance. The study recommends policymakers to support the formulation of asset-based policies that promote access to durable goods, particularly for girls and adolescents from low-income families.

Enhancing Medical Education through the "Distribute, Discuss, and Develop" Method: A Comparative Study of Small-Group Discussions.

Background Small-group discussions (SGDs) are pivotal in medical education, facilitating the development of critical thinking, communication skills, and teamwork. However, traditional SGDs face challenges such as scalability and maintaining student engagement. This study aims to evaluate the "Distribute, Discuss, and Develop" (3D) method for enhancing learning outcomes in medical education. Methods A single-blinded interventional study was conducted with 125 first-year Bachelor of Medicine and Bachelor of Surgery students, who were divided into intervention and control groups through random assignment. The intervention group employed the 3D method across two thematic units: hematology and muscle nerve physiology. The study assessed learning outcomes using pre- and posttests, class-average normalized gain ("g"), and feedback questionnaires to capture student perceptions of interaction, communication enhancement, and session summarization. Results The intervention group showed significantly improved learning outcomes in both thematic units, with larger effect sizes (hematology: 1.55; muscle nerve physiology: 1.4) compared to the control group. The normalized gain "g" indicated a medium effectiveness level for the intervention group in both themes, suggesting enhanced learning. Feedback questionnaires revealed higher satisfaction levels within the intervention group regarding interaction, communication skills, and session summarization. Conclusions The 3D method addresses the challenges faced by traditional SGDs, providing a scalable and engaging approach to medical education. By fostering more effective student-centered learning, the method enhances the comprehension of complex physiological concepts and improves communication skills. The 3Dmethod significantly improves learning outcomes, interaction, and communication skills in medical education. This innovative approach to SGDs offers a promising strategy for enhancing the educational experience in medical schools, supporting the development of more articulate and professionally competent medical graduates.

Stratified Patient Profiling for Vedolizumab Effectiveness in Crohn's Disease: Identifying Optimal Subgroups for Enhanced Treatment Response in the EVOLVE Study.

This analysis evaluated the relative performance of vedolizumab and anti-tumor necrosis factor alpha (anti-TNFα) agents in subpopulations of biologic therapy-naive patients with Crohn's disease (CD) and assessed whether patients in whom vedolizumab would have a larger treatment effect vs anti-TNFα agents could be identified. Data were from EVOLVE, a real-world, multicountry, retrospective cohort study of patients with inflammatory bowel disease who initiated first-line biologic treatment with vedolizumab (n = 195) or anti-TNFα agents (n = 245). Prediction models for time to clinical remission were developed in vedolizumab- and anti-TNFα-treated patients and used to estimate effect scores, a metric of predicted comparative efficacy, for each patient. Patients were ranked by effect scores and potential subpopulations were investigated. Simplified rules to identify these subpopulations were also developed using classification tree analysis. Among all patients, median time to clinical remission was 7.8months (vedolizumab) and 11.1months (anti-TNFα) (P < 0.05). Among patients in the top 40% of the effect score distribution, the median time to clinical remission was 4.8months (vedolizumab) vs 18.1months (anti-TNFα) (adjusted hazard ratio 2.0, 95% confidence interval 1.3-2.9). A simplified rule for identifying a subpopulation more likely to benefit from vedolizumab was based on having an ongoing CD exacerbation, no prior emergency visits, and non-stricturing disease. Subpopulations of biologic-naive patients with CD in whom vedolizumab appeared to have a larger effect relative to anti-TNFα agents for the outcome of clinical remission were identified. Validation of the identified subpopulations and simplified rules are warranted to confirm these findings. NCT03710486. Graphical Abstract available for this article.

Progressive Circuit Hyperexcitability in Mouse Neocortical Slice Cultures with Increasing Duration of Activity Silencing.

Forebrain neurons deprived of activity become hyperactive when activity is restored. Rebound activity has been linked to spontaneous seizures in vivo following prolonged activity blockade. Here, we measured the time course of rebound activity and the contributing circuit mechanisms using calcium imaging, synaptic staining, and whole-cell patch clamp in organotypic slice cultures of mouse neocortex. Calcium imaging revealed hypersynchronous activity increasing in intensity with longer periods of deprivation. While activity partially recovered 3 d after slices were released from 5 d of deprivation, they were less able to recover after 10 d of deprivation. However, even after the longer period of deprivation, activity patterns eventually returned to baseline levels. The degree of deprivation-induced rebound was age-dependent, with the greatest effects occurring when silencing began in the second week. Pharmacological blockade of NMDA receptors indicated that hypersynchronous rebound activity did not require activation of Hebbian plasticity. In single-neuron recordings, input resistance roughly doubled with a concomitant increase in intrinsic excitability. Synaptic imaging of pre- and postsynaptic proteins revealed dramatic reductions in the number of presumptive synapses with a larger effect on inhibitory than excitatory synapses. Putative excitatory synapses colocalizing PSD-95 and Bassoon declined by 39 and 56% following 5 and 10 d of deprivation, but presumptive inhibitory synapses colocalizing gephyrin and VGAT declined by 55 and 73%, respectively. The results suggest that with prolonged deprivation, a progressive reduction in synapse number is accompanied by a shift in the balance between excitation and inhibition and increased cellular excitability.