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Objectives This article observes the mean daily dose of fentanyl required for adequate sedation in critically ill, mechanically ventilated children randomized to receive dexmedetomidine or placebo. Methods We conducted Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multicenter, double-blind, randomized, placebo-controlled, dose-escalating trial. We enrolled children aged 35 weeks postmenstrual to 17 years (inclusive) admitted across 13 pediatric multidisciplinary and cardiac intensive care units. Adequate sedation was based on a State Behavioral Score and Richmond Agitation-Sedation Scale of –1 or lower. Only the first two dexmedetomidine dosing cohorts opened for enrollment, due to early trial closure during the coronavirus 2019 pandemic. Thirty children were randomized over 13 months and included in the analyses. Results Demographic and baseline characteristics were not different between dexmedetomidine and placebo cohorts. Similarly, mean daily fentanyl use was not different, using an unadjusted mixed regression model that considered treatment, time, and a treatment-by-time interaction. Adverse events and safety events of special interest were not different between cohorts. Conclusion The DOSE trial revealed that dexmedetomidine added to fentanyl does not impact safety and may not spare fentanyl use in critically ill children, although the trial did not meet its recruitment goals, due to early closure during the coronavirus 2019 pandemic. More rigorous inpatient pediatric trials like DOSE that study critically ill, mechanically ventilated children are needed. Despite the many obstacles faced, the DOSE trial presents challenges from which the greater research community can learn and use to optimize future therapeutic trials in children.

BACKGROUND AND OBJECTIVE Improved survival has shifted research focus toward understanding alternate PICU outcomes, including neurocognitive and functional changes. Bronchiolitis is a common PICU diagnosis, but its neuro-functional outcomes have not been adequately described in contemporary literature. The objective of the study is to describe the epidemiology and associated clinical characteristics of acute neuro-functional morbidity (ANFM) in critical bronchiolitis. METHODS Patients RESULTS Among 417 children, 16.7% had ANFM, predominantly swallow difficulties (95.7%). Children with ANFM had lower weight (5.9 [4.4–8.2] vs 7.7 [5.5–9.7] kg, P = .001), longer LOS (6.6 [2.5–13.3] vs 1.9 [0.9–3.5] days, P < .001), intubation (51.4% vs 6.1%, P < .001) and high-risk status (37.1% vs 8.4%, P < .001). Among 362 low risk subjects, ANFM was identified in 44 (12%). In a multivariate logistic regression model, high-risk status, intubation, and ICU LOS were associated with ANFM. ANFM persisted to hospital discharge in 46% of cases. CONCLUSIONS One out of 6 patients with critical bronchiolitis had documentation consistent with ANFM at PICU discharge. Risk factors included previous neurologic conditions, longer LOS, and intubation. Many were low-risk and/or did not require intubation, indicating a risk for neuro-functional morbidities despite moderate acuity.

Norge blir stadig et mer mangfoldig samfunn og dette reflekteres i den norske skolen. For å kunne imøtekomme alle elevene i skole må derfor våre pedagogiske og didaktiske tilnærminger tilpasses. In denne masteroppgaven har det yrkesfaglige klasserommet blitt undersøkt i et forsøk på å begynne og forstå hvordan språklig diversitet, eller flerspråklighet, kan bidra til utviklingen av interkulturell kommunikativ kompetanse. Masterstudien tar for seg et semi-strukturert fokusgruppe intervju med 12 elever fra en engelskklasse fra første året på yrkesfag. Formålet med studien er å bringe frem elevperspektivet til flerspråklige elever, å undersøke hvordan språklig diversitet kan bidra til interkulturell kompetanse utvikling, og å diskutere transspråking teori som en tilnærming til undervisning i den mangfoldige skolen. Hovedfunnene indikerer at språklig diversitet både implisitt og eksplisitt kan bidra til utviklingen av interkulturell kommunikativ kompetanse i flerspråklige klasserom. Basert på deltagerens rapporterte erfaringer ser det ut til at interkulturelle perspektiver kan utvikles på bakgrunn av flerspråklighet, og at interkulturelle språkpraksiser hos flerspråklige utvikles basert på språklig diversitet i engelskundervisningen. I tillegg indikerer konklusjonene at transpråklige tilnærminger kan videreføre utviklingsprosessen av interkulturell kommunikativ kompetanse. Due to an increasingly diverse Norwegian society, the educational context has changed. The pedagogical and didactic approaches to the modern-day classroom must therefore make the appropriate adjustments. In this master’s thesis, the Norwegian vocational classroom has been explored to begin to understand how linguistic diversity, or multilingualism, can contribute to the development of intercultural communicative competence. The thesis study: Developing intercultural communicative competence through linguistic diversity in the English subject: A study of the impact of multilingualism in the Norwegian vocational classroom, consists of one semi-structured focus group interview with 12 students from a vocational English class in upper secondary school in Norway. The main goals of the study are to bring forward the multilingual student perspective, to research how diversity can contribute to intercultural competency development, and to discuss translingual theory as an approach to teaching with diversity. The main conclusions drawn indicate that linguistic diversity can contribute to the development of intercultural communicative competence, both implicitly and explicitly. The main findings indicate that practices of multilingual students develop due to linguistic diversity, and that perspectives to some extent are influenced by linguistic diversity’s contribution in the English subject classroom. Additionally, the conclusions suggest that translingual approaches to English language teaching could contribute to these processes.

Timely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting.The three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects.Twenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation.Study start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved.gov #: NCT03938857.

Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Analgesia and sedation are commonly administered to critically ill children to treat pain, provide amnesia, and facilitate interaction with mechanical ventilation and other therapeutic interventions. The development of pain and sedation assessment tools validated in critically ill children has optimized analgosedation delivery. While improved critical care has decreased mortality, new morbidities, including those secondary to prolonged analgosedation administration, are being identified. Tolerance is positively associated with synthetic opioids and continuous infusions. Drug dose and duration of exposure to opioids, benzodiazepines, and dexmedetomidine correlate with increased risk for iatrogenic withdrawal syndrome. Management strategies include multimodal analgesia, regional anesthesia, targeted sedation to reduce drug exposure, IWS screening with validated tools, and slow weaning of analgosedative infusions with or without transition to intermittent receptor-specific replacement agents. Large-scale studies need to be performed to identify drug dosing regimens and develop clinical practice guidelines to prevent and manage tolerance and withdrawal.