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Integration of multitiered academic, behavioral, and social-emotional efforts, such as the implementation of a Comprehensive, Integrated, Three-Tiered (Ci3T) model of prevention, is critical for supporting student development across domains of functioning. In particular, universal behavior screening has been shown to predict outcomes across these domains and as such is foundational to integrated systems. Thus, districts and schools are committed to continuing to learn how to implement behavior screening effectively and efficiently. As such, the purpose of this first qualitative study of systematic screening for behavior was to explore perspectives on benefits, challenges, and opportunities in behavior screening as gathered from members of school- and district-based leadership teams who were currently implementing Ci3T. Both individual interviews and focus groups were conducted, and thematic analysis was employed to identify themes that could be used to enhance the implementation and use of behavior screening. Ci3T Leadership Team members indicated knowledge about behavior screening procedures and relayed challenges with respect to using behavior screening data. Taken together, a need emerged for broader professional learning for all school staff members around increasing knowledge and use of behavior screening data. We discuss limitations and directions for future research.

Cholangiocarcinoma is a form of hepatobiliary cancer with an abysmal prognosis. Despite advances in our understanding of cholangiocarcinoma pathophysiology and its genomic landscape, targeted therapies have not yet made a significant impact on its clinical management. The low response rates of targeted therapies in cholangiocarcinoma suggest that patient heterogeneity contributes to poor clinical outcome. Here we used mass spectrometry–based phosphoproteomics and computational methods to identify patient-specific drug targets in patient tumors and cholangiocarcinoma-derived cell lines. We analyzed 13 primary tumors of patients with cholangiocarcinoma with matched nonmalignant tissue and 7 different cholangiocarcinoma cell lines, leading to the identification and quantification of more than 13,000 phosphorylation sites. The phosphoproteomes of cholangiocarcinoma cell lines and patient tumors were significantly correlated. MEK1, KIT, ERK1/2, and several cyclin-dependent kinases were among the protein kinases most frequently showing increased activity in cholangiocarcinoma relative to nonmalignant tissue. Application of the Drug Ranking Using Machine Learning (DRUML) algorithm selected inhibitors of histone deacetylase (HDAC; belinostat and CAY10603) and PI3K pathway members as high-ranking therapies to use in primary cholangiocarcinoma. The accuracy of the computational drug rankings based on predicted responses was confirmed in cell-line models of cholangiocarcinoma. Together, this study uncovers frequently activated biochemical pathways in cholangiocarcinoma and provides a proof of concept for the application of computational methodology to rank drugs based on efficacy in individual patients. Significance: Phosphoproteomic and computational analyses identify patient-specific drug targets in cholangiocarcinoma, supporting the potential of a machine learning method to predict personalized therapies.

Background Fluid therapy-the administration of fluids to maintain adequate organ tissue perfusion and oxygenation-is essential in patients admitted to the intensive care unit (ICU) with traumatic brain injury. We aimed to quantify the variability in fluid management policies in patients with traumatic brain injury and to study the effect of this variability on patients' outcomes.Methods We did a prospective, multicentre, comparative effectiveness study of two observational cohorts: CENTER-TBI in Europe and OzENTER-TBI in Australia. Patients from 55 hospitals in 18 countries, aged 16 years or older with traumatic brain injury requiring a head CT, and admitted to the ICU were included in this analysis. We extracted data on demographics, injury, and clinical and treatment characteristics, and calculated the mean daily fluid balance (difference between fluid input and loss) and mean daily fluid input during ICU stay per patient. We analysed the association of fluid balance and input with ICU mortality and functional outcome at 6 months, measured by the Glasgow Outcome Scale Extended (GOSE). Patient-level analyses relied on adjustment for key characteristics per patient, whereas centre-level analyses used the centre as the instrumental variable.Findings 2125 patients enrolled in CENTER-TBI and OzENTER-TBI between Dec 19, 2014, and Dec 17, 2017, were eligible for inclusion in this analysis. The median age was 50 years (IQR 31 to 66) and 1566 (74%) of patients were male. The median of the mean daily fluid input ranged from 1middot48 L (IQR 1middot12 to 2middot09) to 4middot23 L (3middot78 to 4middot94) across centres. The median of the mean daily fluid balance ranged from -0middot85 L (IQR -1middot51 to -0middot49) to 1middot13 L (0middot99 to 1middot37) across centres. In patient-level analyses, a mean positive daily fluid balance was associated with higher ICU mortality (odds ratio [OR] 1middot10 [95% CI 1middot07 to 1middot12] per 0middot1 L increase) and worse functional outcome (1middot04 [1middot02 to 1middot05] per 0middot1 L increase); higher mean daily fluid input was also associated with higher ICU mortality (1middot05 [1middot03 to 1middot06] per 0middot1 L increase) and worse functional outcome (1middot04 [1middot03 to 1middot04] per 1-point decrease of the GOSE per 0middot1 L increase). Centre-level analyses showed similar associations of higher fluid balance with ICU mortality (OR 1middot17 [95% CI 1middot05 to 1middot29]) and worse functional outcome (1middot07 [1middot02 to 1middot13]), but higher fluid input was not associated with ICU mortality (OR 0middot95 [0middot90 to 1middot00]) or worse functional outcome (1middot01 [0middot98 to 1middot03]).Interpretation In critically ill patients with traumatic brain injury, there is significant variability in fluid management, with more positive fluid balances being associated with worse outcomes. These results, when added to previous evidence, suggest that aiming for neutral fluid balances, indicating a state of normovolaemia, contributes to improved outcome. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

We report findings from a multistate survey of 720 faculty and staff from 25 elementary schools in five districts across three states and geographic regions participating in an IES Network grant examining integrated tiered systems. In this preregistered study, we replicated and extended previous inquiry examining educators’ views of (1) implementation of core components of their school’s Comprehensive, Integrated, Three-Tiered (Ci3T) model of prevention; and (2) preference for professional learning (content and avenue). Results indicated more than half of respondents indicated high levels of implementation of core features of Ci3T across Tiers 1, 2, and 3. Educators reported high levels of implementation for 10 out of 19 research-based educational practices used within tiered systems with a statistically significant relation between ratings of implemented practices and the desire for support with most practices. Respondents identified their top three areas for professional development needed in the coming year as behavior deescalation techniques, small-group social skills instruction, and strategies for supporting students with internalizing behavior patterns. For potential professional learning avenues, respondents’ top ratings were in-district, during-school workshops, course for college credit on-line, teacher collaboratives/networks, and one-to-one coaching or mentoring. There were many similarities among educators’ ratings across implementation year and state. Low levels of implementation across many core Ci3T and common educational practices were reported by educators working within the most experienced schools. We conclude with a discussion of implications, limitations, and future directions. Supplementary Information The online version contains supplementary material available at 10.1007/s43494-021-00049-z.

The Gibco™ CTS™ Rotea™ Counterflow Centrifugation System is an automated cell processing device developed for manufacturing cell therapy products. The developer (Scinogy Pty Ltd) collaborated with Thermo Fisher Scientific to successfully launch the product in late 2020, completing product development from concept to international sales in

Purpose: This study aimed to determine the prevalence and predictors of death or new disability following critical illness. Methods: Prospective, multicentre cohort study conducted in six metropolitan intensive care units (ICU). Participants were adults admitted to the ICU who received more than 24 h of mechanical ventilation. The primary outcome was death or new disability at 6 months, with new disability defined by a 10% increase in the WHODAS 2.0. Results: Of 628 patients with the primary outcome available (median age of 62 [49–71] years, 379 [61.0%] had a medical admission and 370 (58.9%) died or developed new disability by 6 months. Independent predictors of death or new disability included age [OR 1.02 (1.01–1.03), P = 0.001], higher severity of illness (APACHE III) [OR 1.02 (1.01–1.03), P < 0.001] and admission diagnosis. Compared to patients with a surgical admission diagnosis, patients with a cardiac arrest [OR (95% CI) 4.06 (1.89–8.68), P < 0.001], sepsis [OR (95% CI) 2.43 (1.32–4.47), P = 0.004], or trauma [OR (95% CI) 6.24 (3.07–12.71), P < 0.001] diagnosis had higher odds of death or new disability, while patients with a lung transplant [OR (95% CI) 0.21 (0.07–0.58), P = 0.003] diagnosis had lower odds. A model including these three variables had good calibration (Brier score 0.20) and acceptable discriminative power with an area under the receiver operating characteristic curve of 0.76 (95% CI 0.72–0.80). Conclusion: Less than half of all patients mechanically ventilated for more than 24 h were alive and free of new disability at 6 months after admission to ICU. A model including age, illness severity and admission diagnosis has acceptable discriminative ability to predict death or new disability at 6 months.

Background Few studies have assessed the seroprevalence of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among healthcare workers (HCWs) in Africa. We report findings from a survey among HCWs in 3 counties in Kenya. Methods We recruited 684 HCWs from Kilifi (rural), Busia (rural), and Nairobi (urban) counties. The serosurvey was conducted between 30 July and 4 December 2020. We tested for immunoglobulin G antibodies to SARS-CoV-2 spike protein, using enzyme-linked immunosorbent assay. Assay sensitivity and specificity were 92.7 (95% CI, 87.9-96.1) and 99.0% (95% CI, 98.1-99.5), respectively. We adjusted prevalence estimates, using bayesian modeling to account for assay performance. Results The crude overall seroprevalence was 19.7% (135 of 684). After adjustment for assay performance, seroprevalence was 20.8% (95% credible interval, 17.5%–24.4%). Seroprevalence varied significantly (P < .001) by site: 43.8% (95% credible interval, 35.8%–52.2%) in Nairobi, 12.6% (8.8%–17.1%) in Busia and 11.5% (7.2%–17.6%) in Kilifi. In a multivariable model controlling for age, sex, and site, professional cadre was not associated with differences in seroprevalence. Conclusion These initial data demonstrate a high seroprevalence of antibodies to SARS-CoV-2 among HCWs in Kenya. There was significant variation in seroprevalence by region, but not by cadre.

In this article the author reflects on leadership lessons from a 30 year NHS career in local, regional and national roles. He explains how he has used a 6P model to diagnose and respond to the challenges he has encountered, encompassing purpose, patients, people, processes, partners and politics. Readers are encouraged to use the framework and learning from it to inform their own leadership journeys.

Three related and morphologically similar small Psammodromus species (P. hispanicus complex) occur in the Iberian Peninsula and Mediterranean France, Psammodromus hispanicus, Psammodromus occidentalis, and Psammodromus edwarsianus. Despite recent works, overall ranges of the species remain partially uncertain, in particular for Westernmost part of Iberia and South-western France. Here we include data from 15 additional specimens that were sequenced for part of the mitochondrial gene Cytochrome b to allow comparison with published data. We provide genetic confirmation that P. edwarsianus is the species of the complex occurring in France, and that P. occidentalis occurs on coastal and inland Portugal. Within P. occidentalis notable diversity occurs for this marker, which warrants further investigation. Some areas, particularly southern Portugal, still need assessment to clarify the distribution of these mostly cryptic species across the region.

Scholars have long been interested in how social media platforms shape user communication and behavior. We add to this literature by critically analyzing the TikTok platform. We argue that the principles of mimesis—imitation and replication—are encouraged by the platform’s logic and design and can be observed in the (1) user sign-up process and default page, (2) icons and video-editing features, and (3) user and video creation norms. These memetic features alter modes of sociality, contributing to what we theorize as imitation publics on TikTok. This analysis extends the meme’s theoretical and methodological utility by conceptualizing the TikTok platform as a memetic text in and of itself and illustrates a novel type of networked public.

Educational leadership is essential to implement information and communications technologies in schools but the leadership practice of information and communications technologies coordinators, a position role that supports teachers to implement information and communications technologies, appears limited. The present study applies a distributed perspective to leadership and investigates aspects of information and communications technologies coordinator context that would facilitate leadership. Twenty-seven information and communications technologies coordinators were surveyed on their schools’ structures and mechanisms that mediate their leadership practice. Descriptive statistics show that a wide range of structures and mechanisms in different quantities and with different qualities can be available to coordinators. The majority of coordinators have neither additional position roles nor a teaching load, but the coordinators have organizational unit assignments and attend daily, routine interactions. A case study illustrates how specific structures and mechanisms would facilitate leadership for information and communications technologies implementation. It is recommended to design an information and communications technologies coordinator role as a formal position role, for a school to employ more than one information and communications technologies coordinator, and to develop an information and communications technologies coordinator’s teaching load, organizational unit assignments and routine interactions according to school needs. Several possible populations of information and communications technologies coordinators are identified for further research.

Our aim was to determine the demands and consequences of a single session of continuous (CONT) or interval (INT) eccentric cycling. Fourteen healthy males performed ‘work-matched’ CONT and INT eccentric cycling in a cross over design. Measures of maximal voluntary contraction (MVC), resting twitch force, voluntary activation (VA), muscle soreness, and creatine kinase (CK) were taken at baseline, immediately post, and 24, 48, and 72 h post the first exercise bout. The second bout was used to characterise within session demands. Decreases in MVC (INT 19%, CONT 13%), twitch force (INT 31%, CONT 18%), and VA (INT 10%, CONT 6%) were observed immediately post session (p < 0.05). Reductions in twitch force were greater after INT (p < 0.05) and lasted 48 h. Muscle soreness was greater following INT, versus CONT (p < 0.05), although no differences in CK were observed. Metabolic demands (% of V̇O2peak and [BLa]) were greater during INT vs. CONT (32 ± 6% 28 ± 6%; p < 0.001), [BLa] (1.0 ± 0.4 vs. 0.8 ± 0.2 mmol·L-1; p < 0.001), and RPE (12 ± 1 vs. 11 ± 1; p < 0.001), respectively. Total time under tension was 48% greater in CONT compared to INT (p < 0.001), whereas average torque (during exercise) was 40% greater during INT compared to CONT (p < 0.001). Interval eccentric cycling exacerbates muscle soreness, decrements in muscle function, and lengthens recovery compared to a work matched continuous bout, which is attributable to increased force rather than time under tension.

The significant challenges associated with adapting and delivering the co-design process with Bottom of the Pyramid (BoP) citizens are considered in this article, which tests a new “Empathy Building” step within the Trischler et al. seven-step co-design process model. A sequential, three-study mixed-method research design was applied to co-design a social marketing program with BoP citizens and experts, focusing on the problem of school dropout in a community in South Africa. Study 1 undertook the empathy-building step of the co-design process, which involved a 4-month ethnography in a community in South Africa. This study informed several subsequent co-design steps, including resourcing, planning, recruiting, and sensitizing. Study 2 engaged 38 participants (schoolchildren and parents) in a co-design session, challenging them to create a social marketing program for them and people like them. Study 3 delivered an evaluation session with seven key experts. This article contributes to understanding by offering a process to demonstrate how three studies used the (enhanced) co-design framework to provide a solution for a social issue, namely, prevention of school dropout. Finally, this article outlines how co-design can overcome challenges faced to work with BoP citizens through the addition of ethnography and involvement of experts at the fuzzy back-end of the co-design process to examine program implementation feasibility.

Objective: A rare complication of transvaginal synthetic mesh kits is bladder mesh extrusion. Treatment options include abdominal or vaginal surgical mesh excision or endoscopic mesh vaporization. There are very few published studies detailing endoscopic management. This unique case describes how repeated endoscopic mesh vaporization may be required as mesh extrusion may progress. Methods: A 71-year old female with a history of pelvic organ prolapse managed with an anterior transvaginal mesh kit presented years later with persistent urgency incontinence and recurrent acute cystitis. Cystoscopy eventually revealed bladder calculi adherent to extruded mesh. The stones and extruded mesh were vaporized using the Holmium laser on three occasions over 3 years. Results: Our approach offered a minimally invasive technique with short recovery, no use of a catheter post-operatively and maintained original prolapse repair; however, these patients may be at risk of mesh extrusion recurrence. Conclusion: Bladder extrusion of transvaginal pelvic organ prolapse kit mesh is thankfully a rare complication. With no current consensus for treatment of bladder mesh extrusion, the decision to perform complete mesh excision versus endoscopic treatment should be based on the degree and location of the extrusion, the risk of major complications, mesh extrusion recurrence and the patient’s desired outcomes, including recovery time and risk for prolapse recurrence. Endoscopic vaporization of extruded pelvic organ prolapse mesh likely has a higher recurrence rate than vaginal or abdominal excision. The risks and benefits are important to discuss during counseling and informed consent in these difficult cases. Level of evidence: 4

Sports Leaders UK (SLUK) commissioned this study to explore the socio-economic and demographic factors that influence candidates’ access, completion and progression through formal sport leader qualifications. A sample (n = 76,179) of registered sport leaders, who are defined as those qualified to lead safe, purposeful and enjoyable sport/physical activity at an entry level in local communities, was selected from SLUK’s database covering a five year period. Following frequency analysis and binary logistic regression, findings highlighted certain variables (e.g., gender, experience, locality) as strong predictors of qualification completion and candidate progression through the award system. However, socio-economic status was not found to predict award completion or continued engagement. Frequency analysis indicated an inequality of sport leaders identifying as female, Black or minority ethnic, and/or disabled. This research offers some insight into the landscape of the current and potential future workforce, and has determined factors associated with more sustained involvement in UK sport leader roles. Consequently, such findings are thought to offer a valuable insight into the factors impacting the growth and development of the field.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale–Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Acharge pickup detector was developed at the University of Colorado for use in classroom demonstrations and in the dust accelerator at the Institute for Modeling Plasma, Atmospheres and Cosmic Dust (IMPACT). The detector can be used in a physics classroom to help high school and introductory-level physics students connect electromagnetic phenomena with measurement techniques that are common to experimental physics and in electronics courses to demonstrate the use of a charge-sensitive amplifier (CSA). Construction of a similar detector would develop students’ basic machining and electronics skills, which are crucial in most undergraduate experimental physics opportunities. The detector is designed to nondestructively determine the velocity and charge of particles. The detector is compact (8.6 cm x 5.4 cm x 4.1 cm), simple, and lightweight. It is built with off-the-shelf components with simple machining, resulting in a low-cost (∼$100) detector that maintains the high sensitivity (0.2 fC) necessary for characterization of most hypervelocity dust particles, as well as a wide variety of other applications accessible to introductory-level physics students such as charged particles in a dust storm, pith balls, or charged raindrops. This paper focuses on both characterization of the detector using the accelerator at IMPACT and the basics of the undergraduate-level physics principles, electronics principles, mechanical design, and lab applications.

The Actual and the Rational: Hegel and Objective Spirit, by Jean-François Kervégan. Translated by Daniela Ginsburg and Martin Shuster. Chicago: University of Chicago Press, 2018. xxiii + 384 pp.Avicenna and the Aristotelian Left, by Ernst Bloch. Translated by Loren Goldman and Peter Thompson. New York: Columbia University Press, 2019. xxvi +109 pp.Critique of Forms of Life, by Rahel Jaeggi. Translated by Ciaran Cronin. Cambridge, MA: Belknap Press of Harvard University Press, 2018. xx + 395 pp.

Doravirine is a novel, non-nucleoside reverse transcriptase inhibitor that has shown non-inferior efficacy to ritonavir-boosted darunavir, with a superior lipid profile, in adults with HIV who were treatment naive at week 48 in the phase 3 DRIVE-FORWARD trial. Here we present the 96-week data for the study.This randomised, controlled, double-blind, multicentre, non-inferiority, phase 3 study was undertaken at 125 clinical centres in 15 countries. Eligible participants were adults (aged ≥18 years) infected with HIV-1 who were naive to antiretroviral therapy, with a plasma HIV-1 RNA concentration of 1000 copies per mL or higher at screening, and no known resistance to any of the study drugs. Participants were randomly assigned (1:1) using an interactive voice and web response system, stratified by baseline HIV-1 RNA concentration and background nucleoside reverse transcriptase inhibitor therapy, to doravirine (100 mg per day) or ritonavir-boosted darunavir (100 mg ritonavir and 800 mg darunavir per day), both with investigator-selected nucleoside reverse transcriptase inhibitors: emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. Participants and investigators were masked to treatment assignment until week 96. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here we report the key secondary efficacy endpoint of the proportion of participants who achieved this concentration by week 96, assessed in all participants who received at least one dose of any study drug, regardless of whether it was their randomly assigned treatment. We used a US Food and Drug Administration snapshot approach and a margin of 10 percentage points to define the non-inferiority of doravirine to ritonavir-boosted darunavir at 96 weeks. Key safety endpoints were change in fasting serum lipid concentrations, the incidence of adverse events, and time to discontinuation due to an adverse event, assessed in all participants who received at least one dose of any study medication. This study is registered with ClinicalTrials.gov, NCT02275780, and is closed to accrual.Between Dec 1, 2014, and Oct 20, 2015, 1027 individuals were screened, of whom 769 participants were randomly assigned to doravirine (n=385) or ritonavir-boosted darunavir (n=384), and 383 in both groups were given at least one dose of their allocated treatment. Most participants were male (645 [84%] of 766) and white (560 [73%]), with a mean age of 35·2 years (SD 10·6). 292 participants in the doravirine group and 273 in the darunavir group completed 96 weeks of treatment. At week 96, a higher proportion of the doravirine group (277 [73%] of 383) achieved an HIV-1 RNA concentration of less than 50 copies per mL than did of the darunavir group (248 [66%] of 383; difference 7·1%, 95% CI 0·5-13·7). Responses were similar regardless of baseline characteristics. Treatment-emergent resistance to any study drug occurred in two (1%) of 383 participants in the doravirine group and one (1%) of 383 in the ritonavir-boosted darunavir group. Significant differences were seen between treatment groups in mean changes from baseline in LDL cholesterol (-14·6 mg/dL, 95% CI -18·2 to -11·0) and non-HDL cholesterol (-18·4 mg/dL, -22·5 to -14·3). Frequencies of adverse events were similar between groups. No significant treatment difference (log-rank nominal p=0·063) through week 96 was observed in time to discontinuation due to an adverse event. The most common adverse events (week 0-96) were diarrhoea (65 [17%] in the doravirine group vs 91 [24%] in the ritonavir-boosted darunavir group), nausea (45 [12%] vs 52 [14%]), headache (57 [15%] vs 46 [12%]), and upper respiratory tract infection (51 [13%] vs 30 [8%]). Two participants, one in each group, died during treatment; neither death was considered to be related to study medication.These results through 96 weeks support the efficacy and safety results reported previously for doravirine at 48 weeks, supporting the use of doravirine for the long-term treatment of adults with previously untreated HIV-1 infection.Merck.

This work presents an artificial neural network-based linearly regressive technique for the prediction of a temperature rise event caused by a fire in enclosed building environments. The method predicts temperature range in a burning compartment based on the historic fire behavior data modelled via a neural network algorithm. The approach further extends the method by transforming the regression outcome as actionable information for firefighters via a self-organising feature map (SOM) fire-stage-clustering algorithm which categorises the predicted temperature range to provide warnings of any imminent and catastrophic temperature variations. The methodology implements a linear regression artificial neural model to model and predicts catastrophic temperature variations that are a threat to fire-and-rescue personnel in enclosed burning compartments via a ceiling gas-layer temperature acting as an exogenous variable. Based on the predicted temperature window, the SOM classifier maps the output in distinct clusters while isolating spurious prediction spikes and categorising the output to various self-organising threat/warning levels. The model was trained on temperature data captured with pole-mounted sensors in controlled fire training exercises. Tests carried out in actual fire-settings showed the capability of the SOM classifier to generate evacuation warnings for forecasted temperatures exceeding 300 C in 5 - 30 seconds ahead of the occurrences. Tests on these short-term and long-term prediction ranged from 78.31% to 96.27% in accuracy whereas the SOM classifier generated an overall accuracy of 76.92% to 100%. The techniques also showed a high resilience against both false-positives and false-negatives.

The contribution of adverse medication events to clinical deterioration is unknown. This study aimed to determine the frequency and nature of rapid response system (RRS) calls that clinicians perceived were medication-related using RRS quality arm data.Analysis of routine data prospectively collected by clinicians responding to RRS calls in an Australian acute tertiary academic hospital.Between January 2013 and June 2017, 12,221 adult patients triggered the RRS for 25,906 medical emergency team (MET) and 512 code blue calls. Clinicians identified 433 medication-related RRS calls (1.6%) involving 406 patients (3.3%). These included 418 MET calls (1.3 medication-related MET calls per 1000 admissions) and 15 code blue calls (0.045 medication-related code blue calls per 1000 admissions). Medication-related calls occurred earlier in the admission (p = 0.002) and were more common for patients triggering multiple calls during the same admission (p 0.001), compared to non-medication-related calls. Medication-related calls most commonly were triggered by low blood pressure (38.3%) and involved cardiovascular (43.0%) and nervous system medications (36.0%). Dose-related toxicity (n = 178) was the most frequent adverse medication event contributing to medication-related calls.One in 30 patients triggering a RRS call experienced medication-related clinical deterioration, most often due to dose related toxicity of cardiovascular system medications. The perceived frequency and potential preventability of this medication-related harm suggest further research is required to increase recognition of medication-related RRS calls by responding clinicians and to reduce the incidence.

BACKGROUND IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Preclinical studies have shown that combination of radiotherapy and dual immunotherapy with nivolumab and IDO inhibition significantly prolongs survival of mice with an orthotopic glioblastoma [Ladomersky, et al. CCR 2018;24(11):2559-2573]. In a clinical trial in patients with newly diagnosed glioblastoma with unmethylated MGMT we substituted temozolomide for dual immunotherapy combination. METHODS Phase 1 trial [NCT04047706] using a 3 + 3 dose-escalation design. All received standard radiotherapy (30 x 2 Gy) with addition of once daily oral BMS-986205 and intravenous nivolumab (240mg every 2 weeks) begining on day 1 of radiotherapy and continuing until disease progression or intolerance. BMS-986205 dosing was increased from 50 mg to 100 mg. DLT period encompasses 6 weeks of radiotherapy and the 4 subsequent weeks. Immunocorrelatives being conducted before and after treatment include mass spectrometry for tryptophan and kynurenine levels, immunohistochemistry of resected tumor, and RNA-sequencing and flow cytometric analysis of PBMCs. RESULTS Twelve patients were treated on 2 dose levels of BMS-986205 (50, 100 mg). Treatment-emergent toxicity was as expected for this population. Three (25%) treatment-related SAEs were reported. Dose limiting toxicity of grade 3 transaminase elevation was observed in 2 patients at the 100 mg dose level, while at lower doses of BMS-986205 no substantial alterations of liver enzymes was observed. No other relevant treatment related toxicity occured. Ongoing immunocorrelative profiling and preliminary outcome data (all patients minimal follow-up >12 months) will be available at the time of the meeting. CONCLUSIONS Dose limiting toxicity of BMS-986205 in combination with nivolumab and radiotherapy is hepatic (reversible) transaminitis. The recommended dose for further investigation is 50 mg. Accrual is ongoing for the MGMT promoter methylated cohort using the same regimen without withholding temozolomide. A randomized phase 2/3 trial is approved within the NRG network.

College governing boards are widely held to be the keystone of institutional strategy and the prime locus of support, challenge and accountability in respect of the actions of the senior Executive. Whilst there are many normative prescriptions about the conditions and arrangements required for effective college governance, relatively little is known about how and to what extent the practices of boards reflect or realise these prescriptions. This paper draws upon a unique research study of eight further education colleges across the four nations of the UK. Following Chia and MacKay and Hendry et al., our ‘strategy as practice’ approach gives primacy to emergence and immanence through board practices. Video and observational data, supplemented by some interview and documentary data are used to develop an understanding of governing practices. Our analysis suggests that current normative prescriptions lack the conceptual sophistication required to support governing as it really happens. We offer a reconceptualisation of both strategy and accountability suggesting that the latter includes lateral, inward- and outward-facing functions that make conflicting demands on governors. We argue that these distinctions are vital in enabling further positive development of governing in the college sector.

Highlights • Internal displacement due to conflict or violence can have profound health impacts. • IDPs tend to experience worse health outcomes than other conflict-affected populations. • That reflects the particular vulnerabilities of IDPs relative to these other populations. • Health interventions need to take account of the specific vulnerabilities of IDPs., We seek to strengthen understanding of the health needs of internally displaced persons (IDPs) in contexts of conflict or violence. Based upon a scoping review, our paper identified limited evidence on IDP health, but nevertheless indicates that IDPs tend to experience worse health outcomes than other conflict-affected populations across a range of health issues; and this is due to the particularly vulnerable situation of IDPs relative to these other populations, including reduced access to health services. Further research is required to better understand these needs and the interventions that can most effectively address these needs.

BackgroundAntimicrobial resistance (AMR) poses a major threat to human health. Although rates of AMR have risen significantly in adults over the past few years, increasing rates of AMR are now being seen in children. Antimicrobial stewardship (AMS) is a highly effective approach to tackling AMR;however few paediatric AMS initiatives have focused on antibiotic prescribing in an Emergency Department (ED) setting. There are data to suggest that rates of antibiotic prescribing for respiratory tract infections (RTIs) is higher in children presenting to emergency departments than in those presenting with comparable disease severity to primary care.ObjectivesThe focus of this study was to evaluate the impact of two sequential antimicrobial stewardship interventions on antibiotic prescribing for children aged

Background Outcome selection underpins clinical trial interpretation. Inconsistency in outcome selection and reporting hinders comparison of different trials' results, reducing the utility of research findings. Methods We conducted an iterative consensus process to develop a set of Core Outcome Measures for Perioperative and Anaesthetic Care (COMPAC), following the established Core Outcome Measures for Effectiveness Trials (COMET) methodology. First, we undertook a systematic review of RCTs in high-impact journals to describe current outcome reporting trends. We then surveyed patients, carers, researchers, and perioperative clinicians about important outcomes after surgery. Finally, a purposive stakeholder sample participated in a modified Delphi process to develop a core outcome set for perioperative and anaesthesia trials. Results Our systematic review revealed widespread inconsistency in outcome reporting, with variable or absent definitions, levels of detail, and temporal criteria. In the survey, almost all patients, carers, and clinicians rated clinical outcome measures critically important, but clinicians rated patient-centred outcomes less highly than patients and carers. The final core outcome set was: (i) mortality/survival (postoperative mortality, long-term survival); (ii) perioperative complications (major postoperative complications/adverse events; complications/adverse events causing permanent harm); (iii) resource use (length of hospital stay, unplanned readmission within 30 days); (iv) short-term recovery (discharge destination, level of dependence, or both); and (v) longer-term recovery (overall health-related quality of life). Conclusions This core set, incorporating important outcomes for both clinicians and patients, should guide outcome selection in future perioperative medicine or anaesthesia trials. Mapping these alongside standardised endpoint definitions will yield a comprehensive perioperative outcome framework.

Background: Breast cancer (BC) is a heterogeneous disease comprising different clinical, histopathological, and molecular subtypes. Hormone receptor-positive (HR+) advanced BC cancer, in particular the inflammatory BC (IBC) represents a significant clinical challenge because of the development of endocrine resistance during either adjuvant or metastatic treatment translating to poor outcome. We aim to develop unique PDX tumor models and 3D spheroid/organoid cultures that recapture advanced IBC using pleural effusions or/and circulating tumor cells (CTCs) as tumor resource and that can help understand the mechanism of IBC metastasis for new drug development. Methods: Five samples of pleural effusion-derived tumor cells or circulating tumor cells (CTCs) from three advanced IBC patients were obtained from Northwestern Memorial Hospital to establish IBC PDX tumor model in immunodeficient NSG female mice via subcutaneous or breast fat pad xenografting and develop the derived 3D organoid/spheroid cultures for anti-cancer drug evaluation. STR profiling against with original patient tumor DNA was conducted to confirm the tumor authentication. Results: Three developed IBC PDX tumor models (one HR+-IBC and two triple negative (TN)-IBC) were demonstrated by pathology to have highly heterogeneous characteristics and metastatic features similar to the original patient tumor. NSG mice xenografted with original TN-IBC pleural effusion, or derived spheroid cultures with varying passage numbers (6 passages) manifested different inflammatory clinical symptoms. Mice xenografted with one case of original TN-IBC pleural effusion cells (~40% of tumor-associated macrophages and ~60% of tumor cells) developed palpable tumors and was shown to have the most IBC-like characteristics including reddish skin and ulcerative lesions. They were sacrificed 2 months after xenograft due to declining health. Mice xenografted with >6 passages or Citation Format: Wenan Qiang, Zhangfeng Zhong, Pamela Monahan, Kristy Tse, Youbin Zhang, Qiang Zhang, Lorenzo Gerratana, Andrew Davis, Demirkan Gursel, Reiner Bleher, Jian-Jun Wei, Charles D. James, Thomas V. O’Halloran, Massimo Cristofanilli. Development of patient-derived xenograft tumor models and 3D spheroid culture from advanced hormone receptor-positive inflammatory breast cancer patients for evaluation of new therapeutics [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-06.

Empirical social science research increasingly involves working collaboratively with organisations beyond the university. This paper contributes to the growing international literature on doctoral collaboration by exploring how UK doctoral students in the social sciences negotiate organisational collaborations. We draw on narrative interviews and administrative data to create a series of case-study vignettes. We juxtapose these with a theorisation of disciplinary knowledge practices to show how such collaborations are at once demanding and unpredictable, but also generative of new understanding and insights. We suggest that Burawoy’s (American Sociological Review, 70(1), 4–28, 2005) model of the ‘antagonistic interdependence’ of public, critical, professional and policy sociologies is helpful as a heuristic for conceptualising doctoral student experiences of a range of different (and often contradictory) forms of social scientific knowledge. Our analysis demonstrates that both instrumental and critical forms of social knowledge can emerge from organisational partnerships and placements. We call for further attention to the ‘generative paradoxes’ (Bartunek and Rynes Journal of Management, 40(5), 1181–1201, 2014) and ‘reflective entanglements’ (Jagoda 2016) that result from doctoral collaborations, and for doctoral pedagogies that help students use these experiences to develop criticality and see it as a key skill in social research.

Behavior-specific praise (BSP) is a low-intensity strategy widely used to encourage appropriate behavior. We sought to explore the vast literature base for BSP, which spans 50 years, to better understand for whom and under what conditions BSP has demonstrated effectiveness. We conducted a comprehensive review of school-based intervention studies ( k = 57) involving BSP with school-age students. First, we identified outlets in which these 57 studies (from 52 articles) were featured. Second, we described the 1,947 total student participants and the educational contexts in which these interventions occurred—the vast majority of students were served in general education and many displayed challenging behaviors (e.g., students with emotional and behavioral disorders). Third, we examined how BSP was implemented and evaluated with the Pre-K–12 population, noting three distinct areas of research: teacher-delivered BSP, student-delivered BSP, and professional learning to increase BSP. Fourth, we examined how BSP was employed as an independent and dependent variable, with more than 96% of studies featuring BSP as an outcome measure. Finally, we investigated the extent to which social validity (33 studies), generalization (11 studies), and maintenance (26 studies) were assessed. We conclude with a discussion of limitations and directions for future inquiry.

Purpose: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation. Experimental Design: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. Results: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8+ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy. Conclusions: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.

Background Bipolar percutaneous radiofrequency (RF) is an established method for ablation of distal peripheral branches of the facial nerve to produce weakness of the corrugator muscle. Recent developments to the Serene RF system (Serene Medical, Inc., Pleasanton, CA) allowing for safer and more predictable results highlighted a need for prospective clinical data. Objectives The authors sought to assess the ability of percutaneous RF to safely improve the appearance of dynamic glabellar lines for a minimum of 3 months and up to 1 year. Methods This prospective study enrolled 78 patients across 5 centers in the United States. The most distal branches of the medial and lateral facial nerve innervation to the brow depressor/corrugator complex were treated. Follow-up was at 3 days by telephone and in-office at 7 days and 3, 6, 9, and 12 months posttreatment. Patients were evaluated employing the Merz scale for dynamic glabellar lines. Results At 3 months, 93.6% of patients had a ≥1-point Merz scale improvement in dynamic glabellar lines based on independent, blinded review. Sustained ≥2-point improvement was present in 60% and 20% of patients at 3 and 12 months, respectively. Overall satisfaction remained >60% through 6 months and >50% at 12 months. All device- or procedure-related adverse events were mild (90%) or moderate (10%) and resolved without medical intervention. Conclusions Bipolar percutaneous RF may be adopted in conjunction with surgery or as an office-based procedure where it can serve as a minimally invasive alternative to, or in concert with, Botulinum Toxin A therapy. Level of Evidence: 4

BACKGROUND: Ependymomas (EPNs) are the third most common brain tumor in children. These tumors are resistant to available chemotherapeutic treatments, therefore new effective targeted therapeutics must be identified. Increasing evidence shows epigenetic alterations including histone posttranslational modifications (PTMs), are associated with malignancy, chemotherapeutic resistance and prognosis for pediatric EPNs. In this study we examined histone PTMs in EPNs and identified potential targets to improve chemotherapeutic efficacy. METHODS: Global histone H3 lysine 4 trimethylation (H3K4me3) levels were detected in pediatric EPN tumor samples with immunohistochemistry and immunoblots. Candidate genes conferring therapeutic resistance were profiled in pediatric EPN tumor samples with micro-array. Promoter H3K4me3 was examined for two candidate genes, CCND1 and ERBB2, with chromatin-immunoprecipitation coupled with real-time PCR (ChIP-PCR). These methods and MTS assay were used to verify a relationship between H3K4me3 levels and CCND1 and ERBB2, and to investigate cell viability in response to chemotherapeutic drugs in primary cultured pediatric EPN cells. RESULTS: H3K4me3 levels positively correlate with WHO grade malignancy in pediatric EPNs and are associated with progression free survival in patients with posterior fossa group A EPNs (PF-EPN-A). Reduction of H3K4me3 by silencing its methyltransferase SETD1A, in primary cultured EPN cells increased cell response to chemotherapy. CONCLUSIONS: Our results support the development of a novel treatment that targets H3K4me3 to increase chemotherapeutic efficacy in pediatric PF-EPN-A tumors.

In this systematic literature review, we examined the effects of coaching (e.g., written, emailed, visual, video, and self-monitored performance feedback; in vivo bug-in-ear prompting; combinations) teachers and other educators to increase their use of behavior-specific praise, a low-intensity teacher-delivered strategy previously determined to be a potentially evidence-based practice based on Council for Exceptional Children’s (CEC) Standards for Evidence-Based Practices in Special Education. Research has shown that traditional lecture-style short-duration professional development does not typically lead to lasting change in teacher behavior, but follow-up observations with continued support (e.g., school-wide professional development for all, small group support for some, individualized support for a few) are much more likely to produce desired outcomes. As such, we examined the evidence base for coaching educators to increase behavior-specific praise by applying CEC quality indicators and standards, and concluded that coaching educators to increase behavior-specific praise meets CEC guidelines to be considered an evidence-based practice. Educational implications, limitations, and future directions are presented.

Background In hospitals, rapid response systems (RRSs) identify patients who deteriorate and provide critical care at their bedsides to stabilise and escalate care. Medications, including oral and parenteral pharmaceutical preparations, are the most common intervention for hospitalised patients and the most common cause of harm. This connection between clinical deterioration and medication safety is poorly understood. Objectives To inform improvements in prevention and management of clinical deterioration, this review aimed to examine how medications contributed to clinical deterioration and how medications were used in RRSs. Review methods A scoping review was undertaken of medication data reported in studies of clinical deterioration or RRSs in diverse hospital settings between 2005 and 2017. Bibliographic database searches used permutations of “rapid response system,” “medical emergency team,” and keyword searching with medication-related terms. Independent selection, quality assessment, and data extraction informed mapping against four medication themes: causes of deterioration, predictors of deterioration, RRS use, and management. Results Thirty articles were reviewed. Quality was low: limited by small samples, observational, single-centre designs and few primary medication-related outcomes. Adverse drug reactions and potentially preventable medication errors, involving sedatives, analgesics, and cardiovascular agents, contributed to clinical deterioration. While sparsely reported, outcomes included death and escalation of care. In children, administration of antibiotics or nebulised medications appeared to predict subsequent deterioration. Cardiovascular medications, sedatives, and analgesics commonly were used to manage deterioration but further detail was lacking. Despite reported potential for patient harm, evaluation of medication management systems was limited. Conclusions Medications contributed to potentially preventable clinical deterioration, with considerable harm, and were common interventions for its management. When assessing deteriorating patients or caring for patients who require escalation to critical care, clinicians should consider medication errors and adverse reactions. Studies with more specific medication-related, patient-centred end points could reduce medication-related deterioration and refine RRS medication use and management.

This article builds on the previous articles in this special issue to explore two related concepts – a ‘UK policy laboratory’ and ‘expansive policy learning’, with a specific focus on further education (FE) and skills. We argue that the potential for a UK policy laboratory in this area is based primarily on a new balance between the forces of convergence and divergence across the four countries of the UK. In this ‘goldilocks zone’ lie opportunities for policy learning. The methodology of the UK FE and Skills Inquiry, on which this article draws, attempted to model the conditions of the UK policy laboratory by involving a rich mix of social partners and highlighting the importance of national contexts and how these can inform differing approaches to common challenges. The Inquiry also identified ‘interesting practice’ that may form the basis of an initial ‘common project’ across the different systems. However, its pursuit will require shifts towards the more collaborative approach to FE and skills that characterises the three smaller countries of the UK. In this variegated political environment, we conclude by speculating on the wider conditions for the permanent development of a UK policy laboratory (or laboratories) and expansive forms of policy learning.

Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas are categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter or longer PFS at FDR-adjusted p < 0.05. Using Cytoscape/Reactome FI software, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the seventeen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. As monotherapy, the effects of docetaxel on meningioma were attenuated by multidrug resistance protein 1 (ABCB1) and Cytochrome P450 1B1 (CYP1B1). Docetaxel at 2µM augment double-stranded DNA damage caused by irradiation in vitro, leading to increased cell death. In animal model, low doses of docetaxel and radiation therapy had synergistic effects, increasing survival of mice intracranially implanted with human meningioma cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.

Meeting technology-based policy goals without sufficient lead time may present several technology, regulatory and market-based challenges due to the speed of technological adoption in existing and emerging markets. Installing incremental amounts of technologies, e.g., cleaner fossil, renewable or transformative energy technologies throughout the coming decades, may prove to be a more attainable goal than a radical and immediate change the year before a policy goal is set to be in place. This notion of steady installation growth over acute installations of technology to meet policy goals is the core topic of discussion for this research. This research operationalizes this notion by developing the theoretical underpinnings of regulatory and market acceptance delays by building upon the common Technology Readiness Level (TRL) framework and offers two new additions to the research community. The Regulatory Readiness Level (RRL) and Market Readiness Level (MRL) frameworks were developed. These components, collectively called the Technology, Regulatory and Market (TRM) readiness level framework allow one to build new constraints into existing Integrated Assessment Models (IAMs). A system dynamics model was developed to illustrate the TRM framework. The framework helps identify the factors, and specifically the rate at which we must support technology development, necessary to meet our desired technical and policy goals in the coming decades.

The Dust Coordinate Sensor (DCS) is a dual detector instrument located on the beamline of the 3 MV hypervelocity dust accelerator at the University of Colorado Institute for Modeling Plasma, Atmospheres and Cosmic Dust (IMPACT). This instrument non-destructively measures the three-dimensional trajectories of charged, hypervelocity (3–8 km/s), micron-sized dust particles in flight by utilizing the image charge induced on grids of wire electrodes. Where previous peak detection was typically limited to dust particles carrying charges > ∼ 100 fC, new signal processing techniques developed for DCS allow for effective trajectory measurements on particles carrying charges as small as 6 fC. The new signal processing also effectively eliminates false signal detections completely. The position measurements are matched by timestamp to the charge and velocity for each launched dust particle. Verification of the system was performed with independent impact location measurements on a target placed in the beamline. These measurements agree to within 1 mm2 of the predicted locations using DCS trajectories. This study demonstrates the capability of the instrument including new processing methods. Precise trajectory measurement along the beamline enables new options for instrument calibration, scientific experiments, and improvement of the accelerator performance.