A study protocol for a multicentre, prospective, before-and-after trial evaluating the feasibility of implementing targeted SEDation after initiation of mechanical ventilation in the emergency department (The ED-SED Pilot Trial).

INTRODUCTION: Sedation is a cornerstone therapy in the management of patients receiving mechanical ventilation and is highly influential on outcome. Early sedation depth appears especially influential, as early deep sedation is associated with worse outcome when compared with light sedation. Our research group has shown that patients receiving mechanical ventilation in the emergency department (ED) are exposed to deep sedation commonly, and ED sedation depth is impactful on intensive care unit (ICU) care and clinical outcomes. While extensive investigation has occurred for patients in the ICU, comparatively little data exist from the ED. Given the influence that ED sedation seems to carry, as well as a lack of ED-based sedation trials, there is significant rationale to investigate ED-based sedation as a means to improve outcome. METHODS AND ANALYSIS: This is a multicentre (n=3) prospective, before-and-after pilot trial examining the feasibility of implementing targeted sedation in the immediate postintubation period in the ED. A cohort of 344 patients receiving mechanical ventilation in ED will be included. Feasibility outcomes include: (1) participant recruitment; (2) proportion of Richmond Agitation-Sedation Scale (RASS) scores in the deep sedation range; (3) reliability (agreement) of RASS measurements performed by bedside ED nurses; and (4) adverse events. The proportion of deep sedation measurements before and after the intervention will be compared using the χ2 test. Logistic regression will be used to compare before-and-after differences, adjusting for potential confounders. The inter-rater correlation coefficient will be used to assess paired observations between a study team member and bedside ED nurses, and to describe reliability of RASS measurements. ETHICS AND DISSEMINATION: The Human Research Protection Office at Washington University in St. Louis School of Medicine has approved the study. The publication of peer-reviewed manuscripts and the presentation of abstracts at scientific meetings will be used to disseminate the work. REGISTRATION: ClinicalTrials.gov identifier NCT04410783; Pre-results.

Delirium prevention and treatment in the emergency department (ED): a systematic review protocol.

INTRODUCTION: Delirium is a dangerous syndrome of acute brain dysfunction that is common in the emergency department (ED), especially among the geriatric population. Most systematic reviews of interventions for delirium prevention and treatment have focused on inpatient settings. Best practices of effective delirium care in ED settings have not been established. The primary objective of this study is to identify pharmacologic and non-pharmacologic interventions as applied by physicians, nursing staff, pharmacists and other ED personnel to prevent incident delirium and to shorten the severity and duration of prevalent delirium in a geriatric population within the ED. METHODS AND ANALYSIS: Searches using subject headings and keywords will be conducted from database inception through June 2020 in MEDLINE, EMBASE, Web of Science, PsychINFO, CINAHL, ProQuest Dissertations and Theses Global and Cochrane CENTRAL as well as grey literature. Database searches will not be limited by date or language. Two reviewers will identify studies describing any interventions for delirium prevention and/or treatment in the ED. Disagreements will be settled by a third reviewer. Pooled data analysis will be performed where possible using Review Manager. Risk ratios and weighted difference of means will be used for incidence of delirium and other binary outcomes related to delirium, delirium severity or duration of symptoms, along with 95% CIs. Heterogeneity will be measured by calculating I2, and a forest plot will be created. If significant heterogeneity is identified, metaregression is planned using OpenMeta to identify possible sources of heterogeneity. ETHICS AND DISSEMINATION: This is a systematic review of previously conducted research; accordingly, it does not constitute human subjects research needing ethics review. This review will be prepared as a manuscript and submitted for publication to a peer-reviewed journal, and the results will be presented at conferences. PROSPERO TRIAL REGISTRATION NUMBER: CRD42020169654.

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.

Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.

Elevated Blood Lead Levels in Infants and Children in Haiti, 2015.

OBJECTIVE: Few studies have reported blood lead levels (BLLs) in Haitian children, despite the known presence of lead from environmental factors such as soil, water, leaded paint and gasoline, improperly discarded batteries, and earthquakes. We sought to determine the prevalence of elevated blood lead levels (EBLLs) among healthy Haitian children. METHODS: We enrolled children aged 9 months to 6 years from 3 geographic areas in Haiti (coastal, urban, and mountain) from March 1 through June 30, 2015. We obtained anthropometric measurements, household income, potential sources of lead exposure, and fingerstick BLLs from 273 children at 6 churches in Haiti. We considered a BLL ≥5 µg/dL to be elevated. RESULTS: Of 273 children enrolled in the study, 95 were from the coastal area, 78 from the urban area, and 100 from the mountain area. The median BLL was 5.8 µg/dL, with higher levels in the mountain area than in the other areas ( P < .001). BLLs were elevated in 180 (65.9%) children. The prevalence of EBLL was significantly higher in the mountain area (82 of 100, 82.0%; P < .001) than in the urban area (42 of 78, 53.8%) and the coastal area (56 of 95, 58.9%; P < .001). Twenty-eight (10.3%) children had EBLLs ≥10 µg/dL and 3 (1.1%) children had EBLLs ≥20 µg/dL. Exposure to improperly discarded batteries ( P = .006) and living in the mountain area ( P < .001) were significant risk factors for EBLLs. CONCLUSIONS: More than half of Haitian children in our study had EBLLs. Public health interventions are warranted to protect children in Haiti against lead poisoning.

Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.

Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activates the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoform switch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595.

HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer.

PURPOSE: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury. EXPERIMENTAL DESIGN: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted. RESULTS: The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10(-5) for maximum on-treatment ALT (MaxALT); P = 4.8 × 10(-4) for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10(-5) for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10(-4) for ALT > 3× ULN, P = 9.8 × 10(-3) for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10(-5) for MaxALT, P = 5.1 × 10(-6) for time to ALT > 3×ULN event, P = 5.8 × 10(-6) for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation. CONCLUSIONS: These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients.

RhoA is essential for maintaining normal megakaryocyte ploidy and platelet generation.

RhoA plays a multifaceted role in platelet biology. During platelet development, RhoA has been proposed to regulate endomitosis, proplatelet formation, and platelet release, in addition to having a role in platelet activation. These processes were previously studied using pharmacological inhibitors in vitro, which have potential drawbacks, such as non-specific inhibition or incomplete disruption of the intended target proteins. Therefore, we developed a conditional knockout mouse model utilizing the CRE-LOX strategy to ablate RhoA, specifically in megakaryocytes and in platelets to determine its role in platelet development. We demonstrated that deleting RhoA in megakaryocytes in vivo resulted in significant macrothrombocytopenia. RhoA-null megakaryocytes were larger, had higher mean ploidy, and exhibited stiff membranes with micropipette aspiration. However, in contrast to the results observed in experiments relying upon pharmacologic inhibitors, we did not observe any defects in proplatelet formation in megakaryocytes lacking RhoA. Infused RhoA-null megakaryocytes rapidly released platelets, but platelet levels rapidly plummeted within several hours. Our evidence supports the hypothesis that changes in membrane rheology caused infused RhoA-null megakaryocytes to prematurely release aberrant platelets that were unstable. These platelets were cleared quickly from circulation, which led to the macrothrombocytopenia. These observations demonstrate that RhoA is critical for maintaining normal megakaryocyte development and the production of normal platelets.

Effect of clinic experience on pre-service professionals perceptions of applied special needs services / Effect of clinic experience on pre-service professionals perceptions of applied special needs services

With the understanding that the attitudes and expectations a teacher carries into the classroom directly affect student achievement, this study was administered to evaluate the cognitive affect that clinical experience incorporating individuals with disabilities had on pre-service exercise science professionals. University Students with and withoutexperience in an adapted clinical environment were given surveys covering attitudes and perceptions towards classroom atmosphere, teachers? instructional techniques, inclusion, and self-efficacy. Data were analyzed and used to determine pedagogical implications. Findings suggest that pre-service educators tend to feel unprepared and ill-equipped to work in an inclusive educational environment. Therefore, pre-service teacher programs should ideally include coursework in adaptive education and experiential components such as practicum, experience, and clinical experience. In addition, a school-universitycollaborative relationship can facilitate beneficial outcomes to future educators as well as special needs populations.

Considerando que as atitudes e expectativas que o professor tem na sala de aula afetam diretamente o desempenho do aluno, este estudo teve como objetivo avaliar o efeito cognitivo da experiência clínica acumulada no atendimento com sujeitos portadores de necessidade especiais por profissionais de ciências do exercício. Estudantes universitários com e sem experiência em atividades laborais adaptadas participaram do estudo. Foram fornecidas informações que abrangiam as atitudes e percepções sobre o ambiente da sala de aula, orientações pedagógicas, inclusão e autoeficácia. Os resultados foram analisados e usados para implicações pedagógicas. Os resultados sugerem que os pré-educadores tendem a sentir-se despreparados e mal equipados para trabalhar em um ambiente educacional de inclusão. Portanto, os programas colaborativos de formação de pré-professores deveriam contemplar os cursos de formação educacional, com experiências práticas para o attendimento em ambientes de inclusão social, tais como estágio, experiência de campo e experiência clínica. Além disso, os cursos escola universidade podemoportunizar experiências que facilitem os resultados benéficos para futuros educadores, bem como a atuação junto a populações com necessidades especiais.

Comprehensive treatment of late-onset tibia vara.

BACKGROUND: Late-onset tibia vara (Blount disease) can be difficult to treat because of frequent morbid obesity and associated deformities, including distal femoral varus, proximal tibial procurvatum, and distal tibial valgus, that contribute to lower extremity malalignment. We present a comprehensive approach that addresses all components of the deformity and allows restoration of the anatomic and mechanical axes. METHODS: Fifteen consecutive patients (nineteen lower extremities) with late-onset tibia vara were managed with this comprehensive approach. The mean age of the patients at the time of surgery was 14.9 years, and the mean weight was 113 kg. Standing anteroposterior and lateral radiographs were made preoperatively and at the time of the final follow-up. Preoperatively, the mean mechanical axis deviation was 108 mm, the mean lateral distal femoral angle was 95 degrees , and the mean mechanical medial proximal tibial angle was 71 degrees . In all nineteen extremities, the proximal tibial varus deformity was corrected by means of a valgus osteotomy and application of an Ilizarov ring external fixator. Distal femoral varus was corrected by means of either hemiepiphyseal stapling or valgus osteotomy with blade-plate fixation in thirteen of the nineteen extremities. Distal tibial valgus was treated either with hemiepiphyseal stapling or with varus osteotomy and gradual correction with use of the Ilizarov external fixator in eleven of the nineteen extremities. RESULTS: After a mean duration of follow-up of 5.0 years, the mean mechanical axis deviation had improved to 1 mm (range, 20 to -30 mm), the lateral distal femoral angle had improved to 87 degrees (range, 83 degrees to 98 degrees), and the mechanical medial proximal tibial angle had improved to 88 degrees (range, 83 degrees to 98 degrees ). The mean time required for correction of the proximal tibial varus deformity was thirty-one days, and the external fixator was removed at a mean of 4.5 months postoperatively. All patients had development of one or more superficial pin-track infections (mean, 1.9 pin-site infections per patient). No wound infections, nonunions, or neurovascular complications occurred. Eighteen of the nineteen extremities were pain-free at the time of the final follow-up. CONCLUSIONS: This comprehensive approach allowed restoration of the mechanical and anatomic axes of the lower extremity in patients with late-onset tibia vara, resulting in a resolution of symptoms as a result of normalization of the weight-bearing forces across the knee and ankle. We believe that this approach will decrease the risk of early degenerative arthritis of the knee.