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BACKGROUND: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. METHODS: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. RESULTS: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. CONCLUSIONS: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested 2 mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU Toolbox) in a multi-center, non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week preintervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSβ0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; P < 0.001) and sustained (39.7% to 51.4%, P < 0.001). Mean HbF increased (10.95% to 12.78%; P = 0.03). Self-reported pain frequency reduced (3.54 to 3.35 events/year; P = 0.041). InCharge Health was used ≥1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with ≥1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, P = 0.0045) and weeks 25-36 (1.25 events/patient, P = 0.0015). PDC increased with app use (P < 0.001), with the greatest effect in those with private insurance (P = 0.0078), older subjects (P = 0.033), and those with lower pain interference (P = 0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, 4 unreported), only 11.2% used HU Toolbox ≥1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence can potentially improve adherence and provide clinical benefits. A definitive randomized study is warranted. This trial was registered at www.clinicaltrials.gov as #NCT04080167.

Abstract Voxelotor is a small molecule that reduces the polymerization of sickle hemoglobin by increasing its affinity for oxygen. In patients with sickle cell anemia, it has been postulated that increasing hemoglobin‐oxygen affinity could limit oxygen offloading from hemoglobin, causing an increase in cerebral metabolic stress. To investigate this hypothetical concern, we used multimodal brain imaging to define the effects of voxelotor on cerebral blood flow and oxygen extraction. We followed four patients for 2–5 months during and/or after voxelotor therapy. This study showed no observable increase in cerebral blood flow or oxygen extraction fraction during treatment.

Abstract Objectives The objective of this study is to report the pilot phase of the Targeted Prostate Health Check programme that aims to identify men in the Surrey and Sussex region who have prostate cancer and who failed to be detected during the Covid era. Subjects and methods Men aged 50 to 70, or 45 to 70 if Black or with a family history of prostate cancer, were identified from participating general practitioner (GP) records. Short message service (SMS) texts invited men to visit www.talkprostate.co.uk for information on prostate cancer and give consent to prostate‐specific antigen (PSA) checks coordinated by a third‐party virtual healthcare provider. Elevated age‐related PSA levels, or levels below age‐related thresholds but at 3 ng/mL or more, triggered referral to a rapid access urology clinic. GPs were informed of the results. Results From 1842 text messages inviting 1549 people, 544 men consented to a PSA check. From 500 phlebotomy appointments, 485 (30% of invited men) took the PSA test of whom 68 (14%) were referred with an elevated PSA. After clinical review with multiparametric magnetic resonance imaging (mp‐MRI), 22 patients underwent transperineal biopsies, and prostate cancer was detected in 18 men of whom 17 (95%) had clinically significant cancer. Conclusion Our Targeted Prostate Cancer Health Check system identifies men at risk without burdening primary care. Awareness on prostate cancer risk was raised in 1549 invited men, half of whom were further educated via the registration website. One third of invited men were checked in whom clinically significant prostate cancer was found in 3.5%.

Spaced practice is a recognized effective study approach that fosters mastery of learning and retention of information. In this paper, we share one instructor's experience in introducing a spaced practice intervention in a large general chemistry course and in encouraging students to continue the strategy in the next semester organic chemistry course. The curricular implementation spanned two years during the COVID pandemic and encompassed the instructors' ongoing responsive efforts to enhance students' success. Student perspectives of the perceived value and their use of spaced practice varied with the instructor's conditions of the implementation. Offering spaced practice midway in a semester as an optional approach to homework garnered a positive student response and outcomes. However, moving to a required format for spaced practice in a subsequent semester resulted in much more mixed student feedback and outcomes. The instructor also encouraged and guided students in utilizing the strategy in the following organic chemistry course, and although over 70% of students planned to use it, only about a third actually persisted in the practice. When offering students effective study approaches through course design, instructors also have the challenge and opportunity to cultivate students' intrinsic motivation and self-regulation, skills that enhance their success more broadly. Instructors need to consider investing time in promoting and demonstrating the impact of the method on students' learning, nudging and encouraging students to persevere, and demonstrating metacognitive approaches to learning throughout the course to help students realize its rewards.

As a formally organized field of study, Australian gifted education was established in the early 1980s. Previous studies have examined the quantity and quality of scholarly dissemination and offered the first analyses of the corpus of Australian gifted education empirical research. The purpose of this study is to extend prior findings by investigating the national and international impact of this cumulative body of knowledge using bibliometric methods of analysis. Using Google Scholar as the database to extract our unit of analysis and applying bibliometric analyses, we established growth of citations over time; identified the most-cited authors and peer-reviewed articles; constructed the regional networks who most use Australia's research; and identified citing journals and their corresponding h-index and quartile. The results from this study illustrate the impact and influence of Australian gifted education research nationally and internationally.

Purpose: This study aimed to examine the ways in which physical education teacher education (PETE) prepares preservice physical education teachers (PPETs) to select and implement appropriate assessments. Methods: PPETs (N = 14) enrolled in the secondary teaching methods course at two US universities participated in the study. Semi-structured interviews were completed to collect data concerning how assessment knowledge and skills were taught and learned. Constant content comparison method was used to analyze the data. Results: Two major themes with varying sub-themes emerged from the data: 'Scratching the surface of assessment with unclear learning objectives', and 'Perceiving the importance of assessment, but still not integrate it into instruction' Overall, assessment was not found to conjunctionally taught with instruction. School-based field experiences pertaining to assessment content and pedagogical knowledge were also weak. Conclusions: Minimum assessment knowledge and skills were taught in secondary methods courses with little field experience pertaining to assessment. Future research is needed on examining PETE program content and pedagogy courses to highlight the need for assessment instruction and transform our approaches to preparing PPETs.

Managing disruptive or challenging behavior has been cited as one of the top concerns of early care and education providers. Equipping staff with feasible behavior management strategies is paramount in reducing the occurrence of challenging behaviors in the classroom and negating the need for more intrusive interventions. This article discusses several approaches for preventing severe episodes of challenging behavior altogether, describes intervention procedures that focus directly on functions of challenging behavior, and offers numerous in-the-moment strategies for destructive or dangerous behaviors that must be addresses immediately.

Despite repeated warnings from K-12 online learning scholars, media, and U.S. government bodies about the need for teacher readiness in the face of school disruptions like COVID-19, teacher education programs have largely fallen short in preparing educators for effective online and blended teaching during extended school closures. In this paper, the authors summarize recent suggestions for improving teacher preparation for online and blended K-12 learning environments. The authors present evidence that demonstrates that prior warnings and recommendations did not lead to significant changes in teacher preparation, leaving a gap in essential skills for K-12 online teaching. By integrating these insights with new preparation standards, the authors underscore the critical need to revise teacher education curricula and policies to include K-12 online teaching competencies. The authors argue that equipping teachers with the skills and knowledge to move between in-person and remote teaching is essential for building resilient education systems that are capable of sustaining quality instruction during future disruptions.

Purpose: The study aimed to test the overall changes of health-related fitness (HRF) in minority Chinese college students and to examine HRF differences in gender, race, and year in college. Method: Participants (n = 1320) were minority college students with more than two-thirds females (ie 76.1%), and Hui, Tibetan, and Mongolia consisted of 13.8%, 13.8%, and 11.2%, respectively. Student HRF was tracked for four years. Data were analyzed using multilevel latent growth curve modeling. Results: Muscular strength and endurance were the weakest component in minority college students' HRF, while body mass index was within the category of "excellent". Males outperformed female on all components of HRF. Conclusions: It is suggested that interventions concerning minority females' HRF and muscular strength and endurance for both genders be constructed and tested.

The act of writing involves decision-making that can be challenging for elementary students as they choose ideas, organization structures, and audiences for whom to share their messages. Teachers can support students in their decision-making through providing explicit explanation of the metacognitive decision-making that occurs at each stage of the writing process, using various strategies and skills that writers employ in their craft. To help teachers facilitate these processes, we present the DECIDE Framework to support teachers in demystifying writers' decision-making through strategically planning write-aloud lessons that include metacognitive elements and gradual release of responsibility. This framework supports teachers in making decision-making concrete for students through the use of scripting, scaffolding, and reflecting tools.

Physical educators are often asked to promote whole-school physical activity programming beyond their scheduled class times. Previous research has supported that training in expanded roles would be beneficial during university-based physical education teacher education (PETE) training. In this qualitative study, 13 graduates from a single PETE program that has integrated expanded physical activity into programming shared information about their current programming as physical education teachers in K--12 schools. Campus visits and one-on-one interviews were included. Some practices and values learned during participants' PETE training were evident in graduates' current practices. Aligning with previous studies of professional socialization of physical educators, the resulting themes concluded that (a) strategies and resources gained during PETE training were valued and still used and (b) other ripples of influence, such as administrators and other teachers at their current placement, influenced programming. PETE programming with whole-school physical activity can lead to expanded teaching practices in schools.

This study sought to advance the growing body of research on communication and instruction outside of the college classroom by exploring the rhetorical and relational goals of religious leaders facilitating premarital education about sex (i.e., sexuality, sexual health, and intimacy). Specifically, 47 evangelical Christians who had taught premarital education content (e.g., counseling, courses, and retreats) completed open-ended surveys regarding their goals when communicating about sex and the challenges or barriers to accomplishing their goals. Follow-up interviews were conducted with 16 of the 47 participants about their experiences with the topic. A thematic analysis revealed that participants sought to "counter myths and misconceptions," "teach the emotional-spiritual and redirect the physical," and "create a safe space." Moreover, the challenges they experienced included (couples') discomfort, limited time and expertise, and perceived conflicting teacher-student goals. In all, their efforts to teach "God's design" and the challenges they perceived were filtered through their Christian ideology, indicating the need to continue exploring the role of social identity in teaching-learning contexts.

One strategy for developing science literacy and scientific literacy in young children is through published trade books. To better understand how science literacy and scientific literacy may be represented in elementary classrooms, we investigated children's books that explore science concepts. Specifically, we examined high-quality science trade books that children are likely to encounter in school to see if they could be used to support science literacy and scientific literacy; skills inherent in these types of literacies can arm our students to combat misinformation. Our findings demonstrate that books are not uniform in quality. Consistent with existing research, and in light of our findings, we make the recommendations to support teachers in elevating science trade books from simply serving as opportunities for reading in science to supporting science literacy and scientific literacy.

Using learning objectives to guide course design is often considered an educational best practice, but little research exists that explores how students use them over time and across courses. We surveyed students on their use and perceived value of learning objectives as the semester progressed across four science, technology, engineering, and mathematics (STEM) disciplines, examined students' ability to match exam questions with learning objectives, and analyzed how their course performance related to these qualities. We also gathered instructors' information on their implementation of learning objectives in these courses. We identified distinct disciplinary differences both in students' use and perceived benefit of learning objectives and in instructors' implementation of them. Students in less quantitatively focused courses, i.e., biology and organic chemistry, reported valuing and using learning objectives more than students in more quantitatively focused math and physics courses. Students' ability to match learning objectives with exam questions, however, positively correlated with exam score and final course grade in all our study courses. Our results have implications for considering disciplinary practices for use of learning objectives as instructors design and implement courses, educational researchers plan studies, and assessment specialists formulate institutional assessment plans.

Meta-analysis is commonly used to combine results from multiple clinical trials, but traditional meta-analysis methods do not refer explicitly to a population of individuals to whom the results apply and it is not clear how to use their results to assess a treatment's effect for a population of interest. We describe recently-introduced causally interpretable meta-analysis methods and apply their treatment effect estimators to two individual-participant data sets. These estimators transport estimated treatment effects from studies in the meta-analysis to a specified target population using the individuals' potentially effect-modifying covariates. We consider different regression and weighting methods within this approach and compare the results to traditional aggregated-data meta-analysis methods. In our applications, certain versions of the causally interpretable methods performed somewhat better than the traditional methods, but the latter generally did well. The causally interpretable methods offer the most promise when covariates modify treatment effects and our results suggest that traditional methods work well when there is little effect heterogeneity. The causally interpretable approach gives meta-analysis an appealing theoretical framework by relating an estimator directly to a specific population and lays a solid foundation for future developments.

This study utilized the large-scale, multi-institutional CASSIE dataset to examine the impact of education abroad participation on academic outcomes for first-generation college students. Using robust multivariate matching methodology that effectively minimized self-selection bias, results showed the magnitude of benefit offered by studying abroad was greater for first-generation students than for continuing-generation students. Even after matching on a variety of background and prior achievement variables, first-generation students who studied abroad had higher 4- and 6-year graduation rates, had higher cumulative GPA scores, and took less time to graduate--relative to first-generation students who did not study abroad. These findings suggest that education abroad programming can be leveraged as a high-impact educational practice to promote college completion rates among first-generation students.

The Welsh Government's Welsh language strategy, Cymraeg: A million Welsh speakers [Welsh Government. 2017a. "Cymraeg 2050: A Million Welsh Speakers." Cardiff: Welsh Government], aims to increase the numbers of Welsh speakers to one million by 2050. The creation of new Welsh speakers and immersion education form an integral part of the Welsh Government's language revitalisation strategy and this study revisits new Welsh speakers from the Rhymney Valley, South Wales in 2016/2017 a decade on from the 2006 research study [Hodges, R. 2009. "Welsh Language Use Among Young People in the Rhymney Valley." "Contemporary Wales" 22: 16-35. http://www.ingentaconnect.com/content/uwp/cowa/2009/00000022/00000001/art00004]. This longitudinal research provides further insights into their continuing language journeys, and indicates there has been a sustained reduction in this group's use of Welsh by 2016/2017 due to factors relating to fluency, confidence and a lack of opportunities to use Welsh. However, the results indicate that new speakers play an important role in influencing family language transmission and in increasing language awareness within the workplace. This paper calls for further longitudinal research on new Welsh speakers' language journeys so that this group may be appropriately supported as they make a crucial contribution to language revitalisation in Wales.

This qualitative phenomenological study utilized structured interviews with 23 preschool administrators to explore their beliefs about preschool inclusion and needed resources for providing high-quality preschool inclusion. Themes emerged regarding administrators' beliefs about inclusion, including divergent understandings of inclusion as something that is either for all or for some children. Administrators placed a high value on families' preferences regarding preschool inclusion and at times focused their descriptions of inclusion on logistical aspects of placements and funding. Administrators said they needed additional money and personnel resources to provide high-quality preschool inclusion. Study findings are discussed in the context of the paucity of research on administrator perspectives regarding inclusion and implications for supporting administrators who play a key role in implementing preschool inclusion.

This paper seeks to explain the migration decisions of minority language speakers by investigating motivating factors. Viewed through a language planning lens, the study pushes the parameters of some of the discipline's more recent agency concepts within the context of migration. Semi-structured interviews were conducted with 60 Welsh speakers aged 18-40 who have stayed, left, or returned to the Welsh language 'heartlands' to create a typology representing the diversity in speakers' priorities when deliberating migration decisions. The data shows that the Welsh language is a significant consideration in the migration decisions of some typology groups, however most groups prioritised other factors. It was found that, in some cases, employment was a means of sustaining speakers within the linguistic community or attracting them back, offering much-needed evidence to support key tenets of the Welsh Government's current language strategy. Furthermore, given the likelihood of minority language speakers' decision to stay, leave or return to a language 'stronghold' to increase or limit opportunities to use the language, we argue that migration is an important context for probing the use of agency by minority language speakers at a micro level. Consequently, we contend that migration should receive greater attention from language planning scholars.

BACKGROUND: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration. METHODS: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (

Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden-high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV-/p53wt, and HPV-/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV- tumors, 52 (78.8%) were HPV-/p53mt and 14 (21.2%) were HPV-/p53wt. The HPV-/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV-/p53wt vs 26.3% HPV+ vs. 5.8% HPV-/p53mt, q =0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV-/p53wt vs. 34.2% HPV+ vs. 7.7% HPV-/p53mt, q =0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV-/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup.