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The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

For the investigation of protein-ligand interaction patterns, the current accessibility of a wide variety of sampling methods allows quick access to large-scale data. The main example is the intensive use of molecular dynamics simulations applied to crystallographic structures which provide dynamic information on the binding interactions in protein-ligand complexes. Chemical feature interaction based pharmacophore models extracted from these simulations, were recently used with consensus scoring approaches to identify potentially active molecules. While this approach is rapid and can be fully automated for virtual screening, additional relevant information from such simulations is still opaque and so far the full potential has not been entirely exploited. To address these aspects, we developed the hierarchical graph representation of pharmacophore models (HGPM). This single graph representation enables an intuitive observation of numerous pharmacophore models from long MD trajectories and further emphasizes their relationship and feature hierarchy. The resulting interactive depiction provides an easy-to-apprehend tool for the selection of sets of pharmacophores as well as visual support for analysis of pharmacophore feature composition and virtual screening results. Furthermore, the representation can be adapted to include information involving interactions between the same protein and multiple different ligands. Herein, we describe the generation, visualization and use of HGPMs generated from MD simulations of two x-ray crystallographic derived structures of the human glucokinase protein in complex with allosteric activators. The results demonstrate that a large number of pharmacophores and their relationships can be visualized in an interactive, efficient manner, unique binding modes identified and a combination of models derived from long MD simulations can be strategically prioritized for VS campaigns.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

This study was interested in the level of correspondence between high school students' self-perceptions of academic competence and achievement. The objectives were to (a) identify different profiles of students in terms of correspondence between perceptions of general academic competence and achievement in language arts and mathematics, (b) describe the personal and family characteristics of the students in these profiles, and (c) associate personality traits defined by the Big-Five with these profiles. A latent class analysis and a multinominal logistic regression were conducted on the data collected from 309 ninth and tenth graders. Among the most salient results, five profiles of students were identified, three of which with competence perceptions corresponding with achievement (i.e., high achievers with high self-perceived competence (SPC), average achievers with average SPC, and low achievers with lower SPC) and two with competence perceptions showing no or little correspondence with achievement (i.e., low achievers with higher SPC and average achievers with lower SPC). Also, students scoring high on openness to experience and conscientiousness were more likely to belong to the profile of high achievers with high SPC. These findings contribute to the literature on the possible reasons why students hold accurate or biased self-perceptions of competence.

Youth with conduct problems have poorer academic outcomes than their typically developing peers. The objective of the current study was to examine how sexual minority status was associated with trajectories of teacher-rated mathematics and language arts (i.e., reading and writing) achievement in seven consecutive years across the transition to adolescence among youth with childhood histories of conduct problems (N = 383). Sexual minority status (as assessed via indicators of identity, attraction, or behavior during adolescence in the eighth year of the study) was not associated with initial mathematics or language arts performance at time 1, but was associated with declining mathematics achievement during the transition to adolescence. These findings suggest that sexual minority status is linked to change in some aspects academic achievement among youth already at risk for poorer academic achievement (i.e., youth with conduct problems).

Abstract To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.

This study investigates how individual-level factors contribute to classroom engagement variations of boys and girls across the elementary school years. Classroom engagement was assessed four times between the ages of 7 and 12 years in a large, representative population-based sample (N = 877) using latent growth modeling. Predictors included the sex of the child, the family income, and the mother's educational attainment when the child was 5 months old, along with the child's early receptive vocabulary, numeracy, motor and attentional skills, motivation to learn, and internalizing and externalizing behaviors measured at age 6 years. On average, classroom engagement progressively improved over time. Child vocabulary skills, attention, intrinsic motivation, and externalizing behaviors predicted initial levels of classroom engagement. Child classroom engagement also showed slower progression over time when receptive vocabulary and attentional skills were high. This trend was slightly different when the analyses were conducted separately for boys and girls. Girls with higher attentional skills and fewer externalizing behaviors at age 6 showed slower improvement in classroom engagement throughout elementary school, while boys did not significantly improve in their classroom engagement. Overall, these results suggest that several individual-level factors contribute to classroom engagement. Children with lower levels of receptive vocabulary, attentional skills, and motivation to learn, and those displaying externalizing behavior may benefit from additional help to boost their classroom engagement.

BackgroundDespite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation.MethodsMurine models of NSCLC with distinct driver mutations (KrasG12D/P53+/-/Lkb1-/- (KPL); KrasG12D/P53+/- (KP); and KrasG12D (K)) and varying tumor mutational burden were used to evaluate the efficacy of combination therapy with CCL21-DC ISV plus ICI. Comprehensive analyses of longitudinal preclinical samples by flow cytometry, single cell RNA-sequencing (scRNA-seq) and whole-exome sequencing were performed to assess mechanisms of combination therapy.ResultsISV with CCL21-DC sensitized immune-resistant murine NSCLCs to ICI and led to the establishment of tumor-specific immune memory. Immunophenotyping revealed that CCL21-DC obliterated tumor-promoting neutrophils, promoted sustained infiltration of CD8 cytolytic and CD4 Th1 lymphocytes and enriched progenitor T cells in the TME. Addition of ICI to CCL21-DC further enhanced the expansion and effector function of T cells both locally and systemically. Longitudinal evaluation of tumor mutation profiles revealed that CCL21-DC plus ICI induced immunoediting of tumor subclones, consistent with the broadening of tumor-specific T cell responses.ConclusionsCCL21-DC ISV synergizes with anti-PD-1 to eradicate murine NSCLC. Our data support the clinical application of CCL21-DC ISV in combination with checkpoint inhibition for patients with NSCLC.

Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA1-3. As these patients often have limited English proficiency4-7, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor). Here we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry-sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient's primary language in studies without industry sponsorship was approximately half of that seen in industry-sponsored studies. The results suggest that the cost of consent document translation in trials not sponsored by industry could be a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.

This study investigated the contribution of fine and gross motor skills to academic and attentional performance at school entry among 832 boys and girls. Children were tested on their fine and gross motor skills (locomotor, object control) and their academic performance in receptive vocabulary, number knowledge, and attentional skills at 6 to 7 years old. Results from ordinary least square models adjusted for family income, maternal education attainment, and early cognitive skills at 41 to 48 months revealed that fine motor skills significantly predicted receptive vocabulary, number knowledge, and attention skills. The associations between fine motor skills with receptive vocabulary and attention were stronger for girls than boys. Better performance in locomotor also significantly predicted higher levels of receptive vocabulary while object control was positively associated with attentional skills among girls only. Children with better motor abilities, especially fine motor skills, are more likely to be successful in the areas requiring language, numeracy, and attentional skills. Thus, motor skills should be a focus of interest for increasing academic and attentional skills level at school entry, particularly in girls.

Abstract Background Research has consistently shown that some children are more vulnerable at the time of school readiness. Better understanding the characteristics of these children is therefore important. Most studies have used a variable-based approach, which may mask the presence of small but important subgroups of children with mixed patterns of readiness strengths and weaknesses. Identifying subgroups with mixed readiness patterns using a person-centered approach matters because their developmental trajectories might differ in important ways from children with broader difficulties across all readiness domains. Objective This systematic review attempts to synthesize existing profiles of school readiness conducted on preschool-aged children and to describe how these various profiles are associated with children’s academic achievement and social adjustment during their school years. Specifically, we described how the school readiness profiles vary in number of profiles identified and differences in the specific domains of school readiness. We further describe the school readiness profiles and how they predict later academic and social outcomes. Furthermore, we focus on profile differences between at-risk and non-at-risk preschoolers. Methods Longitudinal studies published between 2005 and 2022 on profiles of school readiness before school entry and at least one subsequent academic and/or social outcomes were extracted from five databases. Eight articles were included in this systematic review out of the 117 screened peer-reviewed articles. Results All the studies incorporated both the cognitive and socioemotional domains of school readiness in their profiles. Fifteen profiles of school readiness at preschool age were identified based on the child level of cognitive and socioemotional skills, with 7 profiles at risk of later academic and social difficulties. Despite variation, children in these at-risk profiles of school readiness shared similar features. Conclusion This literature review provides an exhaustive summary on the number of profiles and domains of school readiness most frequently reported in studies using a person-centered approach. Yielding an in-depth description of at-risk profiles of school readiness can help designing early preventive intervention for these children.

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

IntroductionOsimertinib is an effective treatment for metastatic NSCLC. Occasionally, thoracic radiation therapy (TRT) is delivered to patients receiving osimertinib to treat residual or progressing pulmonary tumors. Anecdotal reports suggest that the delivery of TRT in combination with osimertinib may be associated with a high risk of severe pneumonitis.MethodsA retrospective study was performed at a single academic medical center in the United States to investigate the incidence of severe pneumonitis among patients treated with combined TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of radiation pneumonitis that developed within 6 months of treatment was scored in accordance with the Common Terminology Criteria for Adverse Events version 5.0.ResultsA total of 16 patients were identified who were treated with combined TRT and osimertinib. All had a diagnosis of metastatic NSCLC. Treatment-related grade greater than or equal to 2 pneumonitis developed in 56%, grade greater than or equal to 3 in 37.5%, and grade 4 in 6.3%; no patient developed grade 5 pneumonitis. Median time to any-grade pneumonitis was 29 days (1-84 d); all patients had symptom resolution with expectant management or oral steroid therapies. All patients discovered to have grade greater than or equal to 3 pneumonitis (n = 6) received TRT to tumors located within 2 cm of the proximal bronchial tree, including tumors abutting the proximal bronchial tree (n = 2) and within the mediastinum (n = 1).ConclusionsThe combination of TRT with osimertinib was associated with a high rate of severe pneumonitis that required oral steroid medications. Larger studies are needed to validate these findings and to understand the clinical and treatment factors that influence this risk and how they can be mitigated.

BackgroundAdjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored.MethodsReal-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status.ResultsPD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P

BackgroundDietary behaviors significantly influence health outcomes across populations. Unhealthy diets are linked to serious diseases and substantial economic burdens, contributing to approximately 11 million deaths and significant disability-adjusted life years annually. Digital dietary interventions offer accessible solutions to improve dietary behaviors. However, attrition, defined as participant dropout before intervention completion, is a major challenge, with rates as high as 75%-99%. High attrition compromises intervention validity and reliability and exacerbates health disparities, highlighting the need to understand and address its causes. ObjectiveThis study systematically reviews the literature on attrition in digital dietary interventions to identify the underlying causes, propose potential solutions, and integrate these findings with behavior theory concepts to develop a comprehensive theoretical framework. This framework aims to elucidate the behavioral mechanisms behind attrition and guide the design and implementation of more effective digital dietary interventions, ultimately reducing attrition rates and mitigating health inequalities. MethodsWe conducted a systematic review, meta-analysis, and thematic synthesis. A comprehensive search across 7 electronic databases (PubMed, MEDLINE, Embase, CENTRAL, Web of Science, CINAHL Plus, and Academic Search Complete) was performed for studies published between 2013 and 2023. Eligibility criteria included original research exploring attrition in digital dietary interventions. Data extraction focused on study characteristics, sample demographics, attrition rates, reasons for attrition, and potential solutions. We followed ENTREQ (Enhancing the Transparency in Reporting the Synthesis of Qualitative Research) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used RStudio (Posit) for meta-analysis and NVivo for thematic synthesis. ResultsOut of the 442 identified studies, 21 met the inclusion criteria. The meta-analysis showed mean attrition rates of 35% for control groups, 38% for intervention groups, and 40% for observational studies, with high heterogeneity (I²=94%-99%) indicating diverse influencing factors. Thematic synthesis identified 15 interconnected themes that align with behavior theory concepts. Based on these themes, the force-resource model was developed to explore the underlying causes of attrition and guide the design and implementation of future interventions from a behavior theory perspective. ConclusionsHigh attrition rates are a significant issue in digital dietary interventions. The developed framework conceptualizes attrition through the interaction between the driving force system and the supporting resource system, providing a nuanced understanding of participant attrition, summarized as insufficient motivation and inadequate or poorly matched resources. It underscores the critical necessity for digital dietary interventions to balance motivational components with available resources dynamically. Key recommendations include user-friendly design, behavior-factor activation, literacy training, force-resource matching, social support, personalized adaptation, and dynamic follow-up. Expanding these strategies to a population level can enhance digital health equity. Further empirical validation of the framework is necessary, alongside the development of behavior theory–guided guidelines for digital dietary interventions. Trial RegistrationPROSPERO CRD42024512902; https://tinyurl.com/3rjt2df9

Abstract The psychosocial underpinnings of vaccine hesitancy are complex. Research is needed to pinpoint the exact reasons why people hesitate to vaccinate themselves or their children against vaccine-preventable diseases. One possible reason are concerns that arise from a misunderstanding of vaccine science. We examined the impact of scientific reasoning on vaccine hesitancy and human papillomavirus (HPV) vaccination intent through a cross-sectional study of parents of vaccine-eligible children (N = 399) at immunization clinics in Shanghai, China. We assessed the relationship between science reasoning and both vaccine hesitancy and HPV vaccine acceptance using general additive models. We found a significant association between scientific reasoning and education level, with those with less than a high school education having a significantly lower scientific reasoning that those with a college education (ß = -1.31, p-value = 0.002). However, there was little evidence of a relationship between scientific reasoning and vaccine hesitancy. Scientific reasoning therefore appears not to exert primary influence on the formation of vaccine attitudes among the respondents surveyed. We suggest that research on vaccine hesitancy continues working to identify the styles of reasoning parents engage in when determining whether or not to vaccinate their children. This research could inform the development and implementation of tailored vaccination campaigns.

PurposeIn RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure-response relationship of RAM from RELAY.MethodsPatients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan-Meier method and Cox regression analyses were utilized to evaluate exposure-efficacy by Cmin,1 quartile. Exposure-safety was evaluated by assessing incidence rates for safety parameters by Cmin,ss quartile, with ordered categorical analysis used for ALT/AST only.ResultsAnalyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure-efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the Cmin,1 quartiles were 0.67 (0.45-0.99), 0.77 (0.53-1.12), 0.57 (0.38-0.84), and 0.50 (0.33-0.76). No apparent exposure-safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury.ConclusionsNo association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC.Trial registrationClinicalTrials.gov, NCT02411448.

Separation anxiety symptoms are frequent among preschool-aged children, but it is also a possible gateway for diagnosis of separation anxiety disorder. Early maternal employment after childbirth can increase the risk for the development of separation anxiety symptoms. From an economic perspective, however, securing employment is one effective strategy to ensure child well-being. This study investigated how mothers' participation in the labor force (vs. maternal leave) and the financial state of families when the child was 5 months old was prospectively associated with separation anxiety symptoms. This study is based on 1,295 Canadian families with children assessed longitudinally from 17 months to age 6 on their levels of separation anxiety. Separation anxiety was measured during face-to-face interviews with the mothers. Maternal labor force participation, financial status, and risk factors were measured at 5 months. Results adjusted for propensity scores and for sample weight revealed that children of working mothers, despite having sufficient income (n = 245, 18.9%), were at higher risk of separation anxiety during early childhood. In contrast, maternity leave was most beneficial for children's separation anxiety, whether they were in a family with sufficient income (n = 950, 73.4%) or temporary low income (n = 100, 7.7%). Children of mothers in maternity leave were at risk of heightened separation anxiety only if they experienced chronic economic hardship. Therefore, maternity leave uptake could help prevent the development of separation anxiety. Providing families with opportunity to care for the baby as their main occupation during this sensitive developmental period could help improve children's mental health.

Background: Exposure to childhood trauma may cause several alterations in brain structure and connectivity in adult patients having a major psychiatric disorder. Recent reports have shown that adult patients and young healthy offspring of patients carry similar abnormal retinal response. Because the retina and the brain have the same embryonic origin, the retina gives access to living neuronal tissue that may capture the early neurobiological effect of trauma. Objective: Evaluate the association between exposure to childhood trauma and anomalies in cone (photopic) and rod (scotopic) responses assessed by electroretinography (ERG) in children and adolescents at familial risk (FHRs) of psychosis or mood disorders. Methods: ERG recordings (n=194) undertaken on 134 offspring (Mage of 1st recording=15.7, 49% females) enrolled in our longitudinal study and born to a parent having DSM-IV schizophrenia, bipolar disorder or major depressive disorder were analyzed using repeated measures linear mixed models and applying multiple comparisons. The scotopic and photopic a- and b-wave latencies and amplitudes were recorded. Five types of childhood trauma were assessed prospectively and retrospectively in FHRs: physical abuse, sexual abuse, emotional abuse, neglect and witnessing domestic violence. Results: None of the ERG scotopic or photopic parameters were associated with the global measure of exposure to trauma. However, when analyzing the specific effect of each type of trauma, data suggested that physical abuse in girls would be significantly associated with a prolonged scotopic a-wave latency (p=0.024, ES=0.28) and a trend of association was observed with a prolonged photopic b-wave latency (p=0.099, ES=0.27). Conclusion: Our study did not suggest a substantial effect of childhood trauma on previously reported ERG anomalies in the cone and rod response in youth at familial risk of psychosis or mood disorder. Only one type of trauma i.e., physical violence toward the child, could have a specific effect on the cone and rod prolonged latencies in girls. Methodological limitations are discussed for consideration in interpreting the findings.

PurposeCell-free DNA (cfDNA) offers a noninvasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including minimal residual disease (MRD), recurrence, evolution, and second primary cancers.Experimental designThree simulation datasets were generated from 26 patients with cancer to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n = 76) from patients with cancer (n = 35) with six different cancer types were used for performance validation during various treatments.ResultsWe present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fractions ≥0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fractions ≥0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.ConclusionsOur results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.

ObjectiveThe aim of this study was to investigate whether three facets of lung cancer stigma (internalized stigma, constrained disclosure, and perceived subtle discrimination) uniquely predicted psychological and physical health-related adjustment to lung cancer across 12 weeks. Additionally, self-compassion was tested as a moderator of the stigma-health relationship.MethodAdults receiving oncologic treatment for lung cancer (N = 108) completed measures of lung cancer stigma, self-compassion, depressive symptoms, cancer-related stress, and physical symptom bother. Multivariable linear regression models were used to investigate cross-sectional and longitudinal relationships (at 6- and 12-week follow-up) between indicators of stigma and health-related outcomes, controlling for covariates. Self-compassion was tested as a moderator of these relationships.ResultsAt study entry, higher internalized stigma, constrained disclosure, and perceived subtle discrimination were associated significantly and uniquely with higher depressive symptoms (all p < .05). Constrained disclosure and perceived subtle discrimination were also associated significantly with higher cancer-related stress and higher physical symptom bother at study entry (all p < .05). Furthermore, higher internalized stigma predicted significant increases in depressive symptoms across 12 weeks and in cancer-related stress across 6 and 12 weeks (all p < .05). Higher self-compassion significantly moderated relationships between perceived discrimination and psychological health outcomes at study entry as well as between internalized stigma and increasing depressive symptoms across 12 weeks (all p < .05).ConclusionsResults indicated robust relationships between distinct facets of stigma and health-related adjustment to lung cancer. Supportive care programs that bolster self-compassion may be useful for reducing lung cancer stigma. (PsycInfo Database Record (c) 2022 APA, all rights reserved).