Regulatory functions of homeobox domain transcription factors in fungi.

Homeobox domain (HD) proteins present a crucial involvement in morphological differentiation and other functions in eukaryotes. Most HD genes encode transcription factors (TFs) that orchestrate a regulatory role in cellular and developmental decisions. In fungi, multiple studies have increased our understanding of these important HD regulators in recent years. These reports have revealed their role in fungal development, both sexual and asexual, as well as their importance in governing other biological processes in these organisms, including secondary metabolism, pathogenicity, and sensitivity to environmental stresses. Here, we provide a comprehensive review of the current knowledge on the regulatory roles of HD-TFs in fungi, with a special focus on Aspergillus species.

Prospective implementation of AI-assisted screen reading to improve early detection of breast cancer.

Artificial intelligence (AI) has the potential to improve breast cancer screening; however, prospective evidence of the safe implementation of AI into real clinical practice is limited. A commercially available AI system was implemented as an additional reader to standard double reading to flag cases for further arbitration review among screened women. Performance was assessed prospectively in three phases: a single-center pilot rollout, a wider multicenter pilot rollout and a full live rollout. The results showed that, compared to double reading, implementing the AI-assisted additional-reader process could achieve 0.7-1.6 additional cancer detection per 1,000 cases, with 0.16-0.30% additional recalls, 0-0.23% unnecessary recalls and a 0.1-1.9% increase in positive predictive value (PPV) after 7-11% additional human reads of AI-flagged cases (equating to 4-6% additional overall reading workload). The majority of cancerous cases detected by the AI-assisted additional-reader process were invasive (83.3%) and small-sized (≤10 mm, 47.0%). This evaluation suggests that using AI as an additional reader can improve the early detection of breast cancer with relevant prognostic features, with minimal to no unnecessary recalls. Although the AI-assisted additional-reader workflow requires additional reads, the higher PPV suggests that it can increase screening effectiveness.

Comparing Prognostic Factors of Cancers Identified by Artificial Intelligence (AI) and Human Readers in Breast Cancer Screening.

Invasiveness status, histological grade, lymph node stage, and tumour size are important prognostic factors for breast cancer survival. This evaluation aims to compare these features for cancers detected by AI and human readers using digital mammography. Women diagnosed with breast cancer between 2009 and 2019 from three UK double-reading sites were included in this retrospective cohort evaluation. Differences in prognostic features of cancers detected by AI and the first human reader (R1) were assessed using chi-square tests, with significance at p < 0.05. From 1718 screen-detected cancers (SDCs) and 293 interval cancers (ICs), AI flagged 85.9% and 31.7%, respectively. R1 detected 90.8% of SDCs and 7.2% of ICs. Of the screen-detected cancers detected by the AI, 82.5% had an invasive component, compared to 81.1% for R1 (p-0.374). For the ICs, this was 91.5% and 93.8% for AI and R1, respectively (p = 0.829). For the invasive tumours, no differences were found for histological grade, tumour size, or lymph node stage. The AI detected more ICs. In summary, no differences in prognostic factors were found comparing SDC and ICs identified by AI or human readers. These findings support a potential role for AI in the double-reading workflow.

Attosecond-Angstrom free-electron-laser towards the cold beam limit.

Electron beam quality is paramount for X-ray pulse production in free-electron-lasers (FELs). State-of-the-art linear accelerators (linacs) can deliver multi-GeV electron beams with sufficient quality for hard X-ray-FELs, albeit requiring km-scale setups, whereas plasma-based accelerators can produce multi-GeV electron beams on metre-scale distances, and begin to reach beam qualities sufficient for EUV FELs. Here we show, that electron beams from plasma photocathodes many orders of magnitude brighter than state-of-the-art can be generated in plasma wakefield accelerators (PWFAs), and then extracted, captured, transported and injected into undulators without significant quality loss. These ultrabright, sub-femtosecond electron beams can drive hard X-FELs near the cold beam limit to generate coherent X-ray pulses of attosecond-Angstrom class, reaching saturation after only 10 metres of undulator. This plasma-X-FEL opens pathways for advanced photon science capabilities, such as unperturbed observation of electronic motion inside atoms at their natural time and length scale, and towards higher photon energies.

Costs and benefits of cooperative learning as a universal school-based approach to adolescent substance use prevention.

Substance use during early adolescence implies a greater likelihood of abuse and dependence in later adolescence or adulthood. In turn, substance abuse and dependence are linked to a variety of maladaptive long-term health-related outcomes that imply significant individual and societal costs. In this paper, we evaluated an approach to substance use prevention that relies on the vital role of peers, who comprise a key risk factor for adolescent substance use. This approach (i.e., cooperative learning, CL) focuses on interrupting the process of deviant peer clustering and providing at-risk youth with the opportunity to build social skills and cultivate friendships with low-risk youth. In addition to testing the efficacy of CL in reducing the number of students who become regular substance users, we also conducted a cost-benefit analysis. Using four waves of data from a cluster-randomized trial (N = 15 middle schools, 1890 students, 47.1% female, 75.2% White, 13.9% of students were receiving special education services), we found that significantly lower percentages of students in the intervention (CL) schools became regular users of tobacco, alcohol, and marijuana. We estimated that the reduction in substance use associated with the implementation of CL resulted in total lifetime benefits of between $1027 and $4621 per student (in 2019 dollars), or between $8.79 and $39.54 for each dollar invested in CL. Benefit/cost ratios would go up to $22.54-$101.39 per dollar invested with the continual implementation of CL, assuming retraining every 5 years. Implications and future research directions are discussed.

Peer learning can modify the reciprocal relationship between peer support and victimization in middle school.

INTRODUCTION: This research investigated how peer victimization and support are reciprocally related and how Cooperative Learning (CL) can reverse the progressive cascade that, unchecked, can culminate in youth mental health problems. METHODS: The sample (N = 1890; 53% male) was derived from a randomized trial of CL in 15 middle schools in the United States. Students were recruited in the 7th grade. Structural Equation Modeling (SEM) was used to fit our cross-lag difference score model across four waves of data. RESULTS: The results indicated a reciprocal relationship between peer support and victimization across time, suggesting the potential for negative experiences with peers to become amplified over time in a "vicious cycle," negatively impacting mental health. Students in intervention schools reported significantly higher levels of peer support and lower levels of victimization, suggesting that CL can intervene in this cycle, with salutary effects on mental health; CL also demonstrated direct effects on mental health. CONCLUSIONS: The present study indicates that low peer support can be both a precursor to and an outcome of victimization, serving to maintain a vicious cycle that compounds negative effects on student mental health. Further, results demonstrate how CL can reverse this cycle. We conclude that CL can be of particular importance to the prevention field as a universal mental health program that does not require the associated stigma of identifying youth at elevated risk for referral to treatment programs.

Improving shared decision making for lung cancer treatment by developing and validating an open-source web based patient decision aid for stage I-II non-small cell lung cancer.

The aim of this study was to develop and evaluate a proof-of-concept open-source individualized Patient Decision Aid (iPDA) with a group of patients, physicians, and computer scientists. The iPDA was developed based on the International Patient Decision Aid Standards (IPDAS). A previously published questionnaire was adapted and used to test the user-friendliness and content of the iPDA. The questionnaire contained 40 multiple-choice questions, and answers were given on a 5-point Likert Scale (1-5) ranging from "strongly disagree" to "strongly agree." In addition to the questionnaire, semi-structured interviews were conducted with patients. We performed a descriptive analysis of the responses. The iPDA was evaluated by 28 computer scientists, 21 physicians, and 13 patients. The results demonstrate that the iPDA was found valuable by 92% (patients), 96% (computer scientists), and 86% (physicians), while the treatment information was judged useful by 92%, 96%, and 95%, respectively. Additionally, the tool was thought to be motivating for patients to actively engage in their treatment by 92%, 93%, and 91% of the above respondents groups. More multimedia components and less text were suggested by the respondents as ways to improve the tool and user interface. In conclusion, we successfully developed and tested an iPDA for patients with stage I-II Non-Small Cell Lung Cancer (NSCLC).

A Longitudinal Process Model Evaluating the Effects of Cooperative Learning on Victimization, Stress, Mental Health, and Academic Engagement in Middle School.

Mental health is a significant concern among young people, particularly during the COVID-19 pandemic. Notably, mental health problems can significantly reduce student performance in school, including both engagement and achievement. Both mental health problems and reduced student performance often arise due to peer victimization, which can include teasing, racial- or gender-based discrimination, and/or physical assault. Stress has been proposed as one mechanism through which victimization influences mental health, and stress can also interfere with academic performance at school, including engagement and achievement. To date, however, no research has evaluated longitudinal associations between victimization and stress, and how these longitudinal patterns may impact adolescent behavior and mental health. In this study, we used data from a 2-year cluster randomized trial of cooperative learning to evaluate an etiological process model that includes (1) longitudinal reciprocal effects between victimization and stress, and (2) the effects of both victimization and stress on student mental health and academic engagement. We hypothesized that victimization and stress would have significant reciprocal effects, and that both would predict greater mental health problems and lower academic engagement. We further hypothesized that cooperative learning would have significant effects on all constructs. We found partial support for this model, whereby stress predicted greater victimization, but victimization did not predict increased stress. While both factors were linked to student outcomes, stress was a more powerful predictor. We also found significant salutary effects of cooperative learning on all constructs. The implications of these results for student behavioral and mental health are discussed.

Lessons From a Systematic Literature Search on Diagnostic DNA Methylation Biomarkers for Colorectal Cancer: How to Increase Research Value and Decrease Research Waste?

OBJECTIVES: To improve colorectal cancer (CRC) survival and lower incidence rates, colonoscopy and/or fecal immunochemical test screening are widely implemented. Although candidate DNA methylation biomarkers have been published to improve or complement the fecal immunochemical test, clinical translation is limited. We describe technical and methodological problems encountered after a systematic literature search and provide recommendations to increase (clinical) value and decrease research waste in biomarker research. In addition, we present current evidence for diagnostic CRC DNA methylation biomarkers. METHODS: A systematic literature search identified 331 diagnostic DNA methylation marker studies published before November 2020 in PubMed, EMBASE, Cochrane Library, and Google Scholar. For 136 bodily fluid studies, extended data extraction was performed. STARD criteria and level of evidence were registered to assess reporting quality and strength for clinical translation. RESULTS: Our systematic literature search revealed multiple issues that hamper the development of DNA methylation biomarkers for CRC diagnosis, including methodological and technical heterogeneity and lack of validation or clinical translation. For example, clinical translation and independent validation were limited, with 100 of 434 markers (23%) studied in bodily fluids, 3 of 434 markers (0.7%) translated into clinical tests, and independent validation for 92 of 411 tissue markers (22%) and 59 of 100 bodily fluids markers (59%). DISCUSSION: This systematic literature search revealed that major requirements to develop clinically relevant diagnostic CRC DNA methylation markers are often lacking. To avoid the resulting research waste, clinical needs, intended biomarker use, and independent validation should be better considered before study design. In addition, improved reporting quality would facilitate meta-analysis, thereby increasing the level of evidence and enabling clinical translation.

The Longitudinal Relationship Between Peer Relations and Empathy and their Joint Contribution to Reducing Bullying in Middle School: Findings from a Randomized Trial of Cooperative Learning.

The positive peer relations arising from cooperative learning can contribute to the development of affective empathy, which in turn can reduce bullying (Van Ryzin & Roseth, 2019). However, from a theoretical perspective, the direction of effects between peer relations and empathy could be in the opposite direction, or bi-directional. In the current paper, we employed a process-oriented approach (i.e., cross-lag difference score modeling; McArdle, 2009) to investigate the longitudinal relationship between positive peer relations and affective empathy, as well as their joint effect on bullying. Using four waves of data from a cluster randomized trial including 15 middle schools (7 intervention and 8 control schools; N=1,890 students, 47.1% female, 75.2% White), we found a bi-directional or reciprocal relationship between peer relations and affective empathy, and change in both constructs predicted lower levels of bullying. Cooperative learning predicted positive change in peer relations and affective empathy, as well as lower levels of bullying. These results suggest that the structured social interactions that occur during cooperative learning can enhance student interpersonal relations, and simultaneously the experiential skill building of cooperative learning can contribute to a more profound understanding of the emotional states of others. These effects amplify one another and, in turn, significantly reduce bullying in middle school. Given that cooperative learning has already been demonstrated to enhance academic motivation and achievement (Roseth et al., 2008), we argue that cooperative learning offers an effective, attractive alternative to traditional curriculum-based bullying prevention programs (National Library of Medicine [NLM], NCT03119415).

Reciprocated Friendship as a Mediator of the Effects of Cooperative Learning on Peer Victimization in Middle School.

Peer victimization represents a pervasive problem, particularly for students in middle school. Although curriculum-based prevention programs have generated small to moderate effects on victimization, these effects tend to weaken beginning with the transition to middle school. In this study, we evaluated cooperative learning (CL) as a mechanism to prevent victimization, and evaluated reciprocated friendships as a mediator of these effects. Using four waves of data from a cluster randomized trial of CL (7 intervention and 8 control middle schools; N=1,890 students, 47.1% female, 75.2% White), we found that CL significantly reduced victimization after two years, and these effects were mediated by growth in reciprocated friendship in the first year. We conclude that CL can reduce victimization by providing a means for students to engage in extended social interactions with a wider range of peers and thus creating opportunities for students to forge stronger (i.e., reciprocated) friendships.

The Cascading Effects of Reducing Student Stress: Cooperative Learning as a Means to Reduce Emotional Problems and Promote Academic Engagement.

Adolescents, particularly early adolescents, are vulnerable to stress created by negative peer interactions. Stress, in turn, can lead to increased mental health problems and reduced academic engagement, in addition to negative long-term consequences for cognitive development and physical health. Using four waves (2 years) of data from a cluster randomized trial (N = 15 middle schools, 1,890 students, 47.1% female, 75.2% White), we evaluated whether enhancements to peer relations, brought about through carefully structured small-group learning activities (i.e., cooperative learning), could reduce stress and emotional problems and promote academic engagement. We hypothesized that the increased social contact created by cooperative learning would promote greater peer relatedness, reducing student stress and, in turn, reducing emotional problems and promoting academic engagement. Our results confirmed these hypotheses. We conclude that cooperative learning can provide social, behavioral, academic, and mental health benefits for students.

Mediators of Effects of Cooperative Learning on Prosocial Behavior in Middle School.

In this study, we tested the effects of cooperative learning on students' prosocial behavior. Cooperative learning is a small-group instructional technique that establishes positive interdependence among students and, unlike most current school-based programs, does not mandate a formal curriculum. Given the emphasis in cooperative learning on peer reinforcement for positive and helpful behavior during learning activities, we hypothesized that cooperative learning would promote higher levels of prosocial behavior, and that these effects would be mediated by peer relatedness. Using a sample of 1,890 students (47.1% female, 75.2% White) from a cluster randomized trial of 15 middle schools, we found that cooperative learning significantly enhanced prosocial behavior across two years. Mediation was only partial, however, suggesting that additional mechanisms were at work, such as changes to social norms or teacher behavior. Given that cooperative learning has been shown to enhance student engagement and academic achievement in prior research, we argue that cooperative learning should be a central component of teacher training and professional development.

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.

BACKGROUND: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). METHODS: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. DISCUSSION: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. TRIAL REGISTRATION: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Radiomics: from qualitative to quantitative imaging.

Historically, medical imaging has been a qualitative or semi-quantitative modality. It is difficult to quantify what can be seen in an image, and to turn it into valuable predictive outcomes. As a result of advances in both computational hardware and machine learning algorithms, computers are making great strides in obtaining quantitative information from imaging and correlating it with outcomes. Radiomics, in its two forms "handcrafted and deep," is an emerging field that translates medical images into quantitative data to yield biological information and enable radiologic phenotypic profiling for diagnosis, theragnosis, decision support, and monitoring. Handcrafted radiomics is a multistage process in which features based on shape, pixel intensities, and texture are extracted from radiographs. Within this review, we describe the steps: starting with quantitative imaging data, how it can be extracted, how to correlate it with clinical and biological outcomes, resulting in models that can be used to make predictions, such as survival, or for detection and classification used in diagnostics. The application of deep learning, the second arm of radiomics, and its place in the radiomics workflow is discussed, along with its advantages and disadvantages. To better illustrate the technologies being used, we provide real-world clinical applications of radiomics in oncology, showcasing research on the applications of radiomics, as well as covering its limitations and its future direction.

The Effects of Cooperative Learning on Peer Relations, Academic Support, and Engagement in Learning Among Students of Color.

Despite Brown vs. Board of Education, prejudice still exists in the American school system. These attitudes can give rise to negative social experiences for students of color (i.e., discrimination), negatively impacting their mental and physical health and creating disparities in educational outcomes. Rather than seeking to ameliorate these negative experiences, our approach attempts to address the underlying prejudices and, in so doing, reduce these disparities. Using 4 waves of data from a cluster randomized trial (N = 15 middle schools, 1,890 students, 47.1% female, 75.2% White), we hypothesized that cooperative learning, which has been shown to reduce prejudice in previous research, would create positive gains in peer relatedness, perceptions of academic support, and engagement in learning, and that gains would be larger for students of color; our results confirmed these hypotheses. Our findings highlight the potential role of cooperative learning in reducing disparities and creating greater equity in education.

Effects of cooperative learning on peer relations, empathy, and bullying in middle school.

Although researchers have developed prevention programs to reduce bullying, the results are mixed, and this may be due to a degree of uncertainty in their theoretical foundation. In particular, these programs share an emphasis on empathy as a personal attribute that can be enhanced among students through the application of specific curricula that will, in turn, contribute to a reduction in bullying behavior. However, the link between empathy and bullying is unclear, as is the ability of bullying prevention programs to actually impact student empathy. In this study, we used a cluster randomized trial (N = 15 middle schools, 1,890 students, 47.1% female, 75.2% White) to evaluate the impact of cooperative learning on bullying, and we evaluated whether these effects were mediated by empathy and peer relatedness. Our results indicated that cooperative learning can significantly reduce bullying, and that some of this effect is transmitted via enhancements to affective empathy. Cooperative learning also demonstrated significant positive effects on cognitive empathy, but this did not have an effect on bullying. We also found that the effects of cooperative learning on cognitive and affective empathy were mediated by improvements in peer relatedness. These findings add a degree of clarity to the literature, and also represent the first time, as far as we are aware, that an antibullying program has been found to have significant effects on both cognitive and affective empathy.

Beam emittance preservation using Gaussian density ramps in a beam-driven plasma wakefield accelerator.

A current challenge that is facing the plasma wakefield accelerator (PWFA) community is transverse beam emittance preservation. This can be achieved by balancing the natural divergence of the beam against the strong focusing force provided by the PWFA plasma source in a scheme referred to as beam matching. One method to accomplish beam matching is through the gradual focusing of a beam with a plasma density ramp leading into the bulk plasma. Here, the beam dynamics in a Gaussian plasma density ramp are considered, and an empirical formula is identified that gives the ramp length and beam vacuum waist location needed to achieve near-perfect matching. The method uses only the beam vacuum waist beta function as an input. Numerical studies show that the Gaussian ramp focusing formula is robust for beta function demagnification factors spanning more than an order of magnitude with experimentally favourable tolerances for future PWFA research facilities. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.