Search

At mercury (Hg)-contaminated sites, streambank erosion can act as a main mobilizer of Hg into nearby waterbodies.

Supplemental oxygen is an essential part of in-hospital care for most patients hospitalized with SARS-CoV-2 pneumonia. This study seeks to identify hospitalized patients who will require advanced oxygen support (high flow oxygen, CPAP, BiPAP, or mechanical ventilation) within 96 hours of admission using a machine learning model. This information can be useful for hospitals to plan for nurse staffing, as patients will consume more resources and will need more staff assistance. Data from 302 SARS-CoV-2 patients was used to create a classifier to predict whether or not patients would require advanced oxygen support within 96 hours of admission. Of the 302 cases, 211 were randomly selected to train the model, and 91 were randomly selected for testing. Through a labeled dataset, we performed supervised learning by using a random forest ensemble model which included demographic, clinical comorbidities, vitals, and laboratory values. We used 5-fold cross-validation to evaluate our trained model and employed a majority vote decision across the five trained models in order to produce the final prediction for a given patient. Through the models, we yielded results through sensitivity, specificity, positive predictive value, negative predictive value, and F1 score with the 91 cases of training data. An additional 24 cases were used to test the validity of the ensemble consensus model. Approximately 40% of all patients progressed to require advanced oxygen support 96 hours after the initial presentation. Although the insight gained from the model may not definitively predict the course of an individual patient, this model may help hospital administrators plan for staffing needs with a 48- hour lead time. Patients on high oxygen support require high acuity beds, which have increased nurse-topatient ratios. Additional samples may increase its statistical significance. Nevertheless, this model demonstrates the potential and viability of using data science to help manage hospital resources.

Supplemental oxygen is an essential part of in-hospital care for most patients hospitalized with SARS-CoV-2 pneumonia. This study seeks to identify hospitalized patients who will require advanced oxygen support (high flow oxygen, CPAP, BiPAP, or mechanical ventilation) within 96 hours of admission using a machine learning model. This information can be useful for hospitals to plan for nurse staffing, as patients will consume more resources and will need more staff assistance. Data from 302 SARS-CoV-2 patients was used to create a classifier to predict whether or not patients would require advanced oxygen support within 96 hours of admission. Of the 302 cases, 211 were randomly selected to train the model, and 91 were randomly selected for testing. Through a labeled dataset, we performed supervised learning by using a random forest ensemble model which included demographic, clinical comorbidities, vitals, and laboratory values. We used 5-fold cross-validation to evaluate our trained model and employed a majority vote decision across the five trained models in order to produce the final prediction for a given patient. Through the models, we yielded results through sensitivity, specificity, positive predictive value, negative predictive value, and F1 score with the 91 cases of training data. An additional 24 cases were used to test the validity of the ensemble consensus model. Approximately 40% of all patients progressed to require advanced oxygen support 96 hours after the initial presentation. Although the insight gained from the model may not definitively predict the course of an individual patient, this model may help hospital administrators plan for staffing needs with a 48- hour lead time. Patients on high oxygen support require high acuity beds, which have increased nurse-topatient ratios. Additional samples may increase its statistical significance. Nevertheless, this model demonstrates the potential and viability of using data science to help manage hospital resources.

It was well-observed that SARS-CoV-2 may cause a hypercoagulable state in hospitalized patients. Often these hospitalized patients exhibit severe upper respiratory symptoms with hypoxia, requiring high amounts of oxygen support. In this study, we report a young healthy 30-year-old woman with no medical problems, who experienced an embolic stroke due to an otherwise asymptomatic SARS-CoV-2 infection in July 2020. The patient presented to the emergency department after experiencing sudden slurred speech, dizziness, and acute left leg weakness during a social gathering on a river boat the day prior to admission. She also vomited once, non-bilious. The patient had no upper respiratory symptoms and had not been practicing social distancing nor wearing a mask. She did not have any sick contacts or significant travel history. Patient used oral contraceptives but never smoked. The workup included a Computed Tomography (CT) angiogram, an Magnetic Resonance Imaging (MRI) and an Magnetic Resonance Angiography (MRA) of the brain. It was significant for acute stroke with acute intraluminal thrombus causing partial occlusion of the distal basilar artery with left pontine stroke. Given that the onset of symptoms was greater than 4 hours, she was outside of the tissue Plasminogen Activator (tPA) administration window. Patient was also not a candidate for embolectomy as National Institute of Health Stroke Scale (NIHSS) was 3 and the occlusion was partial. SARS-CoV-2 PCR test was positive. D-Dimer level was elevated but CRP was normal. Echocardiogram was unremarkable. The patient had no history of autoimmune disorder. Patient was initially treated with antiplatelet medications aspirin and clopidogrel (Plavix). Her condition improved and she could ambulate with a front wheel walker and stand by to assist. She was discharged four days later with anticoagulation medication rivaroxaban (Xarelto) for 3 months. This case illustrates that patients with an otherwise asymptomatic SARS-CoV-2 infection may still suffer from complications of SARS-CoV-2. Do women on oral contraceptives have higher risk of arterial embolism when infected with SARS-CoV-2? More study is needed.

Photosurfactants have shown considerable promise for enabling stimuli-responsive control of the properties and motion of fluid interfaces. Recently, a number of photoswitch chemistries have emerged to tailor the photoresponsive properties of photosurfactants. However, systematic studies investigating how photoresponsive surfactant behavior depends on the photochemical and photophysical properties of the switch remain scarce. In this work, we develop synthetic schemes and surfactant designs to produce a well-controlled library of photosurfactants to comparatively assess the behavior of photoswitch chemistry on interfacial behavior. We employ photoinduced spreading of droplets at fluid interfaces as a model for such studies. We show that although photosurfactant response is largely guided by expected trends with changes in polarity of the photoswitch, interfacial behavior also depends nontrivially and sometimes counter-intuitively on the kinetics and mechanisms of photoswitching, particularly at the interface of two solvents, as well as on complex interactions with other surfactants. Understanding these complexities enables the design of new photosurfactant systems and their optimization toward responsive functions including triggered spreading, dewetting, and destabilization of droplets on solid and fluid surfaces.

PURPOSE: Patient-reported outcome measurements (PROMs) are increasingly used for cancer patients receiving active treatment, but little is known about the implementation and usefulness of PROMs in cancer survivorship care. This systematic review evaluates how cancer survivors and healthcare providers (HCPs) perceive PROM implementation in survivorship care, and how PROM implementation impacts cancer survivors' health outcomes.METHODS: We systematically searched PubMed/MEDLINE, Embase, CINAHL, Web of Science, and Cochrane Database of Systematic Reviews from database inception to February 2022 to identify randomized and nonrandomized studies of PROM implementation in cancer survivors.RESULTS: Based on prespecified eligibility criteria, we included 29 studies that reported on 26 unique PROMs. The studies were heterogeneous in study design, PROM instrument, patient demographics, and outcomes. Several studies found that cancer survivors and HCPs had favorable impressions of the utility of PROMs, and a few studies demonstrated that PROM implementation led to improvements in patient quality of life (QoL), with small to moderate effect sizes.CONCLUSIONS: We found implementation of PROMs in cancer survivorship care improved health outcomes for select patient populations. Future research is needed to assess the real-world utility of PROM integration into clinical workflows and the impact of PROMs on measurable health outcomes.IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors accepted PROMs. When successfully implemented, PROMs can improve health outcomes after completion of active treatment. We identify multiple avenues to strengthen PROM implementation to support cancer survivors.

CuInSe2 (CIS) has been proposed as an attractive bottom cell candidate in tandem solar cells. However, to justify the coupling with high-performance top cells (e.g., perovskites, GaAs), significant...

Fluctuations in mental and bodily states have both been shown to be associated with negative affective experience. Here we examined how momentary fluctuations in attentional and cardiac states combine to regulate the perception of positive social value. Faces varying in trustworthiness were presented during a go/no-go letter target discrimination task synchronized with systolic or diastolic cardiac phase. Go trials lead to an attentional boosting of perceived trust on high trust and ambiguous neutral faces, suggesting attention both boosted existing and generated positive social value. Cardiac phase during face presentation interacted with attentional boosting of trust, enhancing high trust faces specifically during relaxed diastolic cardiac states. Confidence judgments revealed that attentional trust boosting, and its cardiac modulation, did not reflect altered perceptual or response fluency. These results provide evidence for how moment-to moment fluctuations in top-down mental and bottom-up bodily inputs combine to enhance a priori and generate de novo positive social value.

Background The incidence of positional plagiocephaly has increased significantly over the last two decades, which has caused a service delivery challenge for pediatric neurosurgeons. As a potential solution to the long waitlists for abnormal head shape, a plagiocephaly clinic was established at BC Children's Hospital (BCCH) in Vancouver, Canada. This clinic was supervised by an occupational therapist who had been trained by a neurosurgeon to independently assess and manage patients with a referring diagnosis of positional plagiocephaly. Objectives To determine the efficiency of the BCCH Plagiocephaly Clinic in the management of positional plagiocephaly patients and to investigate the clinic's ability to appropriately identify and refer patients with craniosynostosis to pediatric neurosurgeons for further assessment. Methods A retrospective chart review was conducted to identify patients who were assessed and managed at the BCCH Plagiocephaly Clinic between 2008 and 2014. Data on patient demographics, head shape measurements, and treatment recommendations were collected, and the BC Children's neurosurgical database was cross-referenced to identify craniosynostosis cases missed by the Plagiocephaly Clinic. A descriptive analysis of the clinic's average wait times, severity of the patients' plagiocephaly, and recommended interventions was conducted. In addition, the sensitivity and specificity of the clinic's ability to appropriately refer craniosynostosis patients to pediatric neurosurgery were calculated. Results Of 1752 patients seen in the BC Children's Plagiocephaly Clinic between 2008 and 2014, 66% of patients received counseling about repositioning, 34% were referred for head banding, 19% were referred to physiotherapy for torticollis, and 1.4% were referred to the BC Children's Pediatric Neurosurgery Clinic for suspicion of craniosynostosis. The mean time from referral to first assessment by the Plagiocephaly Clinic was 41 days, and time from referral by the plagiocephaly clinic to diagnosis of craniosynostosis by a pediatric neurosurgeon was 8 days. Pediatric neurosurgeons requested imaging for 6 of the referred patients (25% ). The sensitivity and specificity of the plagiocephaly clinic for referral of craniosynostosis patients to the Pediatric Neurosurgery Clinic were 100 and 99%, respectively. Conclusion The BC Children's Plagiocephaly Clinic is efficient and safe for the initial evaluation and treatment of patients with positional plagiocephaly. The clinic's model decreases wait times, appropriately manages patients with positional plagiocephaly, screens for craniosynostosis with high sensitivity and specificity, and takes pressure off outpatient neurosurgical clinics. This model for assessment of plagiocephaly could be considered in other medical centers.

Background Although many studies have determined that PD-L1 expression by immunohistochemistry can be somewhat predictive of a response to checkpoint inhibitor the impact of specific genomic changes and smoking history in the context of PD-L1 expression is limited. This single-center study examined clinical and genomic factors beyond STK11 and EGFR in patients with advanced non-small cell lung cancer (NSCLC) to determine which patients benefit from therapy with immune checkpoint inhibitors (ICIs). Methods Clinical and genomic features of patients with NSCLC treated with immunotherapy were compiled into a database. Genomic information collected included gene mutations via next generation sequencing, tumor mutation burden (TMB), and PD-L1 tumor proportional scores. Results A total of 131 patients with advanced NSCLC treated with ICIs were examined. Race was not associated with response. A positive response to immunotherapy was associated with smoke year increase (P=0.042). KRAS mutation and MYC amplification were associated with a positive response to immunotherapy while EGFR, RB1, and NF1 mutations were associated with a lack of response. KRAS mutation (P=0.007) and high TMB (P=0.070) were positively associated with smoking history. EGFR mutation was negatively associated with smoking history (P=0.002) . In multivariate analysis controlling for age and smoking history, MYC amplification continued to be the only predictive genomic marker with a trend toward response to therapy (P=0.092) beyond the smoking history. Conclusions Among the clinical and genomic factors examined in this study, smoking status is the most predictive of response to ICIs. Only MYC amplification continued to predict a trend toward response to immunotherapy when controlling for smoking history. Other genomic predictors such as EGFR and KRAS simply reflect their association with smoking. Detailed smoking history and MYC amplification alone can predict response to ICI.

We report the identification of a de novo GABRA1 (R214C) variant in a child with epileptic encephalopathy (EE), describe its functional characterization and pathophysiology, and evaluate its potential therapeutic options. The GABRA1 (R214C) variant was identified using whole exome sequencing, and the pathogenic effect of this mutation was investigated by comparing wild-type (WT) α1 and R214C α1 GABAA receptor-expressing HEK cells. GABA-evoked currents in these cells were recorded using whole-cell, outside-out macro-patch and cell-attached single-channel patch-clamp recordings. Changes to surface and total protein expression levels of WT α1 and R214C α1 were quantified using surface biotinylation assay and western blotting, respectively. Finally, potential therapeutic options were explored by determining the effects of modulators, including diazepam, insulin, and verapamil, on channel gating and receptor trafficking of WT and R214C GABAA receptors. We found that the GABRA1 (R214C) variant decreased whole-cell GABA-evoked currents by reducing single channel open time and both surface and total GABAA receptor expression levels. The GABA-evoked currents in R214C GABAA receptors could only be partially restored with benzodiazepine (diazepam) and insulin. However, verapamil treatment for 24 h fully restored the function of R214C mutant receptors, primarily by increasing channel open time. We conclude that the GABRA1 (R214C) variant reduces channel activity and surface expression of mutant receptors, thereby contributing to the pathogenesis of genetic EE. The functional restoration by verapamil suggests that it is a potentially new therapeutic option for patients with the R214C variant and highlights the value of precision medicine in the treatment of genetic EEs.

Background Status epilepticus (SE) is a common pediatric neurological emergency that requires timely treatment to minimize morbidity and mortality, yet administration of rescue medications is often delayed and underdosed. Seizure action plans (SAPs) outline the steps that should be taken by parents and caregivers in case of SE in order to optimize patient outcomes. Our study determined the uptake of SAPs in a pediatric population with epilepsy and assessed parental interest in a SAP mobile application. Methods A survey was distributed to parents of patients with epilepsy aged 1 month to 19 years at British Columbia Children’s Hospital. Following chart review, univariate and multivariate analyses were performed to identify variables that predict whether patients have SAPs. A systematic search of available mobile applications for epilepsy management was conducted. Results Of 192 participants, 62% have SAPs. On univariate analysis, history of prior SE and male gender increased likelihood of SAP. On logistic regression, Nagelkerke R2 was 0.204 and our model correctly predicted 82% of patients with SAPs. 83% of parents were interested in a SAP mobile application. There are currently 40 mobile applications available for epilepsy management, but only 15% of respondents reported using them. Conclusions There is a need to increase the percentage of patients with epilepsy with SAPs, particularly in those at greater risk of SE. Most parents would find a SAP mobile application valuable in their child’s epilepsy management. There is a gap between the high parental interest in mobile applications for epilepsy management and their current use of such applications.

Oxytocin (OXT) is a neuropeptide that activates the oxytocin receptor (OXTR), a rhodopsin family G-protein coupled receptor. Our localization of OXTR to the retinal pigment epithelium (RPE), in close proximity to OXT in the adjacent photoreceptor neurons, leads us to propose that OXT plays an important role in RPE-retinal communication. An increase of RPE [Ca2+]i in response to OXT stimulation implies that the RPE may utilize oxytocinergic signaling as a mechanism by which it accomplishes some of its many roles. In this study, we used an established human RPE cell line, a HEK293 heterologous OXTR expression system, and pharmacological inhibitors of Ca2+ signaling to demonstrate that OXTR utilizes capacitative Ca2+ entry (CCE) mechanisms to sustain an increase in cytoplasmic Ca2+. These findings demonstrate how multiple functional outcomes of OXT-OXTR signaling could be integrated via a single pathway. In addition, the activated OXTR was able to inhibit the Kir7.1 channel, an important mediator of sub retinal waste transport and K+ homeostasis.

We report the identification of a de novo GABRA1 (R214C) variant in a child with epileptic encephalopathy (EE), describe its functional characterization and pathophysiology, and evaluate its potential therapeutic options. The GABRA1 (R214C) variant was identified using whole exome sequencing, and the pathogenic effect of this mutation was investigated by comparing wild-type (WT) α1 and R214C α1 GABA

Childhood primary angiitis of the central nervous system (cPACNS) is a rare inflammatory disease of brain vessels. The small vessel subtype is diagnosed on brain biopsy and often presents with cognitive and behavioral changes, headaches, and seizures. However, there are few reported cases of super-refractory status epilepticus in children. We present a case of small vessel cPACNS complicated by super-refractory status epilepticus requiring burst suppression for 4 weeks in addition to multiple antiseizure medications and the ketogenic diet. Our patient was also treated with intravenous and oral steroids, intravenous immunoglobulin, and cyclophosphamide before starting maintenance therapy with mycophenolate mofetil. After prolonged rehabilitation, he recovered almost completely and has a normal neurologic examination with rare epileptiform activity on electroencephalogram (EEG). This is one of the longest cases of status epilepticus in small vessel cPACNS in the literature. We illustrate that super-refractory status epilepticus can be the first manifestation of small vessel cPACNS in previously healthy children and that symptomatic management of seizures with concurrent immunosuppression to treat the underlying pathology resulted in favorable neurologic outcomes.

The retinoblastoma gene (RB1) encodes the retinoblastoma (RB) pocket protein that plays an important role in cell cycle progression. Here we determine the frequency and prognostic significance of RB1 mutation in non small cell lung cancer (NSCLC), restricting inclusion to Stage III and IV patients with linked genomic and clinical data. The primary outcome was median overall survival (OS). We identified RB1 mutation in 8.2% of NSCLC patients. The median OS for wild‐type (wt) RB1 was 28.3 months vs 8.3 months for mutant RB1 (Hazard Ratio = 2.59, P = 0.002). Of special interest, RB1 mutation also correlated with lack of response to immunotherapy. Our study focused on RB1 mutation in locally advanced and advanced non small cell lung cancer to better facilitate comparisons with small cell lung cancer (SCLC). In our SCLC cohort, RB1 mutation was identified in 75% of patients and wt RB1 was associated with significantly shorter OS (P = 0.002). The different outcomes of RB1 mutation observed among lung cancer subtypes suggest a more complicated mechanism than simple regulation of cell cycle or response to chemotherapy.

The specialty of anesthesiology will soon adopt the Competence By Design (CBD) approach to residency education developed by the Royal College of Physicians and Surgeons of Canada (RCPSC). A foundational component of CBD is frequent and contextualized assessment of trainees. In 2013, the RCPSC Anesthesiology Specialty Committee assembled a group of simulation educators, representing each of the 17 Canadian anesthesiology residency programs, to form the Canadian National Anesthesiology Simulation Curriculum (CanNASC) Task Force. The goals were to develop, implement, and evaluate a set of consensus-driven standardized mannequin-based simulation scenarios that every trainee must complete satisfactorily prior to completion of anesthesiology residency and certification. Curriculum development followed Kern's principles and was accomplished via monthly teleconferences and annual face-to-face meetings. The development and implementation processes included the following key elements: 1) Curriculum needs assessment: 368 of 958 invitees (38.4%) responded to a national survey resulting in 64 suggested scenario topics. Use of a modified Delphi technique resulted in seven important and technically feasible scenarios. 2) Scenario development: All scenarios have learning objectives from the National Curriculum for Canadian Anesthesiology Residency. Standardized scenario templates were created, and the content was refined and piloted. 3) Assessment: A validated Global Rating Scale (GRS) is the primary assessment tool, informed by using scenario-specific checklists (created via a modified Delphi technique) and the Anesthesia Non-Technical Skills GRS. 4) Implementation: Standardized implementation guidelines, pre-brief/debrief documents, and rater training videos, guide, and commentary were generated. National implementation of the scenarios and program evaluation is currently underway. It is highly feasible to achieve specialty-based consensus on the elements of a national simulation-based curriculum. Our process could be adapted by any specialty interested in implementing a simulation-based curriculum incorporating competency-based assessment on a national scale.

Simulation-based education has gained popularity, yet many faculty members feel inadequately prepared to teach using this technique. Fellowship training in medical education exists, but there is little information regarding simulation or formal educational programs therein. In our institution, simulation fellowships were offered by individual clinical departments. We recognized the need for a formal curriculum in educational theory. Kern’s approach to curriculum development was used to develop, implement, and evaluate the Foundational Elements of Applied Simulation Theory (FEAST) curriculum. Needs assessments resulted in a 26-topic curriculum; each biweekly session built upon the previous. Components essential to success included setting goals and objectives for each interactive session and having dedicated faculty, collaborative leadership and administrative support for the curriculum. Evaluation data was collated and analyzed annually via anonymous feedback surveys, focus groups, and retrospective pre-post self-assessment questionnaires. Data collected from 32 fellows over five years of implementation showed that the curriculum improved knowledge, challenged thinking, and was excellent preparation for a career in simulation-based medical education. Themes arising from focus groups demonstrated that participants valued faculty expertise and the structure, practicality, and content of the curriculum. We present a longitudinal simulation educator curriculum that adheres to a well-described framework of curriculum development. Program evaluation shows that FEAST has increased participant knowledge in key areas relevant to simulation-based education and that the curriculum has been successful in meeting the needs of novice simulation educators. Insights and practice points are offered for educators wishing to implement a similar curriculum in their institution.

A 3,220-g male infant is born at 34 weeks’ gestation by urgent cesarean delivery because of concerns for fetal well-being to a 33-year-old gravida 3 para 1 now 2 mother with serologies significant for O positive, rubella nonimmune, hepatitis B surface antigen negative, rapid plasma reagin nonreactive, human immunodeficiency virus negative, Group B streptococcus status unknown. Resuscitation of the infant is significant for the need for positive pressure ventilation, intubation, chest compressions for 1 minute and bilateral thoracentesis with no drainage of fluid. Pregnancy was complicated by previous herpes simplex virus infection with negative bright light examination at time of delivery, previous Cesarean delivery, and new-onset hydrops fetalis. One week before delivery, ultrasound of the fetus was significant for bilateral pleural effusions, cardiac enlargement, increased middle cerebral artery Doppler flow, and polyhydramnios with an amniotic fluid index of 40. Initial assessment reveals a large-for-gestational age infant with generalized edema. He is placed on the high-frequency oscillator on admission. His abdominal examination is significant for the liver edge palpated 3 cm below the right costal margin. An initial chest radiograph reveals bilateral pleural effusions, with right greater than left and hazy lung fields (Fig 1). A cardiology consultation is urgently requested after admission, and the initial echocardiogram reveals a small patent foramen ovale, a small midseptal muscular ventricular septal defect both with left to right flow, right ventricular hypertrophy with normal function, and a tiny pericardial effusion. Figure 1. Initial chest and abdomen radiograph on admission to the NICU displaying a small left pleural effusion and moderate right pleural effusion. Cardiac size is normal for gestational age. ### Initial Evaluation Initial arterial blood gas is pH 7.36 mm Hg, pCO2 45 mm Hg, pO2 132 mm Hg, HCO3 26 mmol/L with base deficit of 0.2 mmol/L. His initial complete blood count reveals white blood cell count …

Background The objective of this study was to compare the effect of thoracic paravertebral block (TPVB) and local anesthetic (LA) on persistent postoperative pain (PPP) 1 year following breast cancer surgery. Secondary objectives were to compare the effect on arm morbidity and quality of life. Methods Women scheduled for elective breast cancer surgery were randomly assigned to either TPVB or LA followed by general anesthesia. An NRS value of >3 at rest or with movement 1 year following surgery defined PPP. Blinded interim analysis suggested rates of PPP much lower than anticipated, making detection of the specified 20 % absolute reduction in the primary outcome impossible. Recruitment was stopped, and all enrolled patients were followed to 1 year. Results A total of 145 participants were recruited; 65 were randomized to TPVB and 64 to LA. Groups were similar with respect to demographic and treatment characteristics. Only 9 patients (8 %; 95 % CI 4–14 %) met criteria for PPP 1 year following surgery; 5 were in the TPVB and 4 in the LA group. Brief Pain Inventory severity and interference scores were low in both groups. Arm morbidity and quality of life were similar in both groups. The 9 patients with PPP reported shoulder-arm morbidity and reduced quality of life. Conclusions This study reports a low incidence of chronic pain 1 year following major breast cancer surgery. Although PPP was uncommon at 1 year, it had a large impact on the affected patients’ arm morbidity and quality of life.

Background Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting. Procedure To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n = 21) or autologous (n = 15) SCT at our institution between 1982 and 2004. Pathologic classification included: lymphoblastic lymphoma (n = 12), Burkitt lymphoma (BL) (n = 5), diffuse large B-cell lymphoma (n = 4), anaplastic large cell lymphoma (ALCL) (n = 13), peripheral T cell lymphoma (n = 1), and undifferentiated NHL (n = 1). Donor source for allogeneic-SCT recipients was an HLA-matched related donor (n = 15), a matched unrelated donor (n = 4), or a mismatched donor (related n = 1; unrelated n = 1). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR). Results Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-SCT (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 61%, compared with 25% among patients with relapsed/refractory disease (P = 0.019). Conclusions Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease. Pediatr Blood Cancer 2013;60:2018–2024. © 2013 Wiley Periodicals, Inc.

Background Mental practice (MP) is defined as the ‘symbolic rehearsal of a physical activity in the absence of any gross-muscular movements' and has been used in sport and music to enhance performance. In healthcare, MP has been demonstrated to improve technical skill performance of surgical residents. However, its effect on crisis resource management (CRM) skills has yet to be determined. We aimed to investigate the effect of warm-up with MP on CRM skill performance during a simulated crisis scenario. Methods Following ethics board approval, 40 anaesthesia residents were randomized. The intervention group performed 20 min of MP of a script based on CRM principles. The control group received a 20 min didactic teaching session on an unrelated topic. Each subject then managed a simulated cardiac arrest. Two CRM experts rated the video recordings of each performance using the previously validated Ottawa GRS. The time to start chest compressions, administer epinephrine, and give blood was recorded. Results There was no significant difference between the intervention and control groups: total Ottawa GRS score was 24.50 (18.63–28.88 [6.50–34.50]) (median (inter-quartile range [range]) vs 20.50 (13.00–29.13 [6.50–34.50]) (P=0.53); the time to start chest compressions 146.0 s (138.0–231.0 [115.0–323.0]) vs 162.5 s (138.0–231.0 [100.0–460.0]) (P=0.27), the time to epinephrine administration 163.0 s (151.0–187.0 [111.0–337.0]) vs 187.0 s (164.0–244.0 [115.0–310.0]) (P=0.09), and the time to blood administration 220.5 s (130.8–309.0 [92.0–485.0]) vs 252.5 (174.5–398.8 [65.0–527.0]) (P=0.48). Conclusion Unlike technical skills, warm-up with MP does not seem to improve CRM skills in simulated crisis scenarios.

A preoperative machine check is imperative, yet machine faults are missed despite experience. We hypothesized that a simulation training session would improve junior residents’ ability to perform a machine check beyond the level of final year residents who received only didactic training. In 2005, an experiential machine check training session was introduced into residency training at the postgraduate year 1 (PGY-1) level. Three weeks later, the simulation residents were asked to perform a machine check and detect ten preset faults. The control group consisted of PGY-5 residents who had received a didactic anesthesia machine lecture during their residency; these control residents were asked to perform the same machine check as the simulation residents. Data were collected from 2005 to 2008 with each cohort of incoming PGY-1 residents and graduating PGY-5 residents. When the first group of PGY-1 residents became PGY-5 residents in 2009, they were invited to return for a retention test. In all tests, the number of faults detected was recorded, and the machine check was evaluated using a checklist. Thirty-seven simulation residents and 27 control residents participated in the study. Simulation residents had significantly higher checklist scores than the control residents, and they identified more machine faults (both P

OBJECTIVE: To examine the effect of a blended educational intervention (in-class and independent learning modules) developed to enhance Ohio PHN confidence in 25 disaster surge competencies that address the PHN role and skills in Preparedness, Response, and Recovery. DESIGN AND SAMPLE: This was a quasi-experimental one group pre and post design. Participants (N = 54) completed pre- and postintervention surveys to evaluate intervention impact on self-perceived confidence and need for further training in the 25 competencies. MEASURES: Parallel pre and post surveys assessed participant evaluation of confidence and need for further competency training. Paired t tests and repeated measures ANOVA compared pre- and postsurvey results. RESULTS: Confidence in Preparedness, Response, and Recovery PHN disaster surge competencies significantly increased, whereas self-perceived need for further competency training correspondingly significantly decreased. CONCLUSIONS: A blended learning approach to disaster surge training effectively improved PHNs confidence in competency achievement and reduced perceived need for further training. Language: en

Sufu (Suppressor of Fused), a two-domain protein, plays a critical role in regulating Hedgehog signaling and is conserved from flies to humans. A few bacterial Sufu-like proteins have previously been identified based on sequence similarity to the N-terminal domain of eukaryotic Sufu proteins, but none have been structurally or biochemically characterized and their function in bacteria is unknown. We have determined the crystal structure of a more distantly related Sufu-like homolog, NGO1391 from Neisseria gonorrhoeae, at 1.4 A resolution, which provides the first biophysical characterization of a bacterial Sufu-like protein. The structure revealed a striking similarity to the N-terminal domain of human Sufu (r.m.s.d. of 2.6 A over 93% of the NGO1391 protein), despite an extremely low sequence identity of ∼15%. Subsequent sequence analysis revealed that NGO1391 defines a new subset of smaller, Sufu-like proteins that are present in ∼200 bacterial species and has resulted in expansion of the SUFU (PF05076) family in Pfam.

The crystal structure of BT2081 from B. thetaiotaomicron reveals a two-domain protein with a putative carbohydrate-binding site in the C-­terminal domain., BT2081 from Bacteroides thetaiotaomicron (GenBank accession code NP_810994.1) is a member of a novel protein family consisting of over 160 members, most of which are found in the different classes of Bacteroidetes. Genome-context analysis lends support to the involvement of this family in carbohydrate metabolism, which plays a key role in B. thetaiotaomicron as a predominant bacterial symbiont in the human distal gut microbiome. The crystal structure of BT2081 at 2.05 Å resolution represents the first structure from this new protein family. BT2081 consists of an N-terminal domain, which adopts a β-sandwich immunoglobulin-like fold, and a larger C-terminal domain with a β-sandwich jelly-roll fold. Structural analyses reveal that both domains are similar to those found in various carbohydrate-active enzymes. The C-terminal β-jelly-roll domain contains a potential carbohydrate-binding site that is highly conserved among BT2081 homologs and is situated in the same location as the carbohydrate-binding sites that are found in structurally similar glycoside hydrolases (GHs). However, in BT2081 this site is partially occluded by surrounding loops, which results in a deep solvent-accessible pocket rather than a shallower solvent-exposed cleft.

The crystal structure of BT1062 from Bacteroides thetaiotaomicron revealed a conserved fold that is widely adopted by fimbrial components., BT1062 from Bacteroides thetaiotaomicron is a homolog of Mfa2 (PGN0288 or PG0179), which is a component of the minor fimbriae in Porphyromonas gingivalis. The crystal structure of BT1062 revealed a conserved fold that is widely adopted by fimbrial components.

T-cell depleted allogeneic hematopoietic stem cell transplants (TCD-HSCT) have demonstrated durable disease-free survival with a low risk of graft vs. host disease (GVHD) in patients with AML. We investigated this approach in 61 patients with primary refractory or relapsed non-Hodgkin lymphoma (NHL), who underwent TCD-HSCT from January 1992 through September 2004. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, followed by either thiotepa and cyclophosphamide (45 patients) or thiotepa and fludarabine (16 patients). We determined the second-line age-adjusted International Prognostic Index score (sAAIPI) prior to transplant. Median follow-up of surviving patients is 6 years. The 10-year overall (OS) and event-free-survival (EFS) were 50% and 43%, respectively. The relapse rate at 10 years was 21% in patients with chemosensitive disease and 52% in those with resistant disease at time of HSCT. Nine of the 18 patients who relapsed entered a subsequent CR. Overall survival (p=0.01) correlated with the sAAIPI. The incidence of grade II-IV acute GVHD was 18%. We conclude that allogeneic TCD-HSCT can induce high rates of OS and EFS in advanced NHL with a low incidence of GVHD. Furthermore, the sAAIPI can predict outcomes and may be used to select the most appropriate patients for this type of transplant.

The crystal structure of the NGO1945 gene product from N. gonorrhoeae (UniProt Q5F5IO) reveals that the N-terminal domain assigned as a domain of unknown function (DUF2063) is likely to bind DNA and that the protein may be involved in transcriptional regulation., Proteins with the DUF2063 domain constitute a new Pfam family, PF09836. The crystal structure of a member of this family, NGO1945 from Neisseria gonorrhoeae, has been determined and reveals that the N-terminal DUF2063 domain is likely to be a DNA-binding domain. In conjunction with the rest of the protein, NGO1945 is likely to be involved in transcriptional regulation, which is consistent with genomic neighborhood analysis. Of the 216 currently known proteins that contain a DUF2063 domain, the most significant sequence homologs of NGO1945 (∼40–99% sequence identity) are from various Neisseria and Haemophilus species. As these are important human pathogens, NGO1945 represents an interesting candidate for further exploration via biochemical studies and possible therapeutic intervention.

KPN03535 is a protein unique to K. pneumoniae. The crystal structure reveals that KPN03535 represents a novel variant of the OB-fold and is likely to be a DNA-binding lipoprotein., KPN03535 (gi|152972051) is a putative lipoprotein of unknown function that is secreted by Klebsiella pneumoniae MGH 78578. The crystal structure reveals that despite a lack of any detectable sequence similarity to known structures, it is a novel variant of the OB-fold and structurally similar to the bacterial Cpx-pathway protein NlpE, single-stranded DNA-binding (SSB) proteins and toxins. K. pneumoniae MGH 78578 forms part of the normal human skin, mouth and gut flora and is an opportunistic pathogen that is linked to about 8% of all hospital-acquired infections in the USA. This structure provides the foundation for further investigations into this divergent member of the OB-fold family.

Crisis resource management (CRM) skills are a set of nonmedical skills required to manage medical emergencies. There is currently no gold standard for evaluation of CRM performance. A prior study examined the use of a global rating scale (GRS) to evaluate CRM performance. This current study compared the use of a GRS and a checklist as formal rating instruments to evaluate CRM performance during simulated emergencies.First-year and third-year residents participated in two simulator scenarios each. Three raters then evaluated resident performance in CRM using edited video recordings using both a GRS and a checklist. The Ottawa GRS provides a seven-point anchored ordinal scale for performance in five categories of CRM, and an overall performance score. The Ottawa CRM checklist provides 12 items in the five categories of CRM, with a maximum cumulative score of 30 points. Construct validity was measured on the basis of content validity, response process, internal structure, and response to other variables. T-test analysis of Ottawa GRS scores was conducted to examine response to the variable of level of training. Intraclass correlation coefficient (ICC) scores were used to measure inter-rater reliability for both scenarios.Thirty-two first-year and 28 third-year residents participated in the study. Third-year residents produced higher mean scores for overall CRM performance than first-year residents (P0.05), and in all individual categories within the Ottawa GRS (P0.05) and the Ottawa CRM checklist (P0.05). This difference was noted for both scenarios and for each individual rater (P0.05). No statistically significant difference in resident scores was observed between scenarios for both instruments. ICC scores of 0.59 and 0.61 were obtained for Scenarios 1 and 2 with the Ottawa GRS, whereas ICC scores of 0.63 and 0.55 were obtained with the Ottawa CRM checklist. Users indicated a strong preference for the Ottawa GRS given ease of scoring, presence of an overall score, and the potential for formative evaluation.Construct validity seems to be present when using both the Ottawa GRS and CRM checklist to evaluate CRM performance during simulated emergencies. Data also indicate the presence of moderate inter-rater reliability when using both the Ottawa GRS and CRM checklist.

Results of allogeneic hematopoietic stem cell transplantation (HCT) to treat advanced leukemia or myelodysplastic syndrome (MDS) remain poor due to excessive relapse and transplant-related mortality. To improve transplant outcome in this patient population, 43 patients (median age, 46.1 years) with high-risk or advanced lymphoid (n = 5) or myeloid malignancy (n = 38) were prospectively enrolled on a pilot trial of cytoreduction with intravenous busulfan and melphalan followed by an unmodified HLA-A, -B, and –DRβ1–matched related (n = 18) or unrelated (n = 25) HCT. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-four patients had ≥ 5% blasts at the time of HCT; 12 of these had > 20% blasts. Seventeen patients had unfavorable cytogenetics, 8 patients underwent transplantation for secondary MDS or acute myelogenous leukemia, and 4 patients had relapsed after a previous allogeneic transplantation. Although mucositis was the most significant regimen-related toxicity, requiring the addition of folinic acid rescue and failure to receive all 4 doses of methotrexate in 23 patients, the nonrelapse mortality at 30 and 100 days was low at 0% and 16%, respectively. The cumulative incidence of grade II-IV acute GVHD was 24%, and that of extensive chronic GVHD was 7%. With a minimum follow-up of 18 months, the estimated 3-year overall survival is 37% and the estimated disease-free survival (DFS) is 33%. For 18 patients with MDS (≤ RAEB-2) or high-risk myeloproliferative disorder, the estimated 3 year DFS is 61%. These data demonstrate the curative potential of this regimen in patients with high-risk myeloid malignancies.

Purpose Oxytocin (OXT) is recognized as an ubiquitously acting nonapeptide hormone that is involved in processes ranging from parturition to neural development. Its effects are mediated by cell signaling that occurs as a result of oxytocin receptor (OXTR) activation. We sought to determine whether the OXT-OXTR signaling pathway is also expressed within the retina. Methods Immunohistochemistry using cell-specific markers was used to localize OXT within the rhesus retina. Reverse transcriptase PCR and immunohistochemistry were used to assess the expression of OXTR in both human and rhesus retina. Single-cell RT-PCR and Western blot analyses were used to determine the expression of OXTR in cultured human fetal RPE (hfRPE) cells. Human fetal RPE cells loaded with FURA-2 AM were studied by ratiometric Ca(2+) imaging to assess transient mobilization of intracellular Ca(2+) ([Ca(2+)]i). Results Oxytocin was expressed in the cone photoreceptor extracellular matrix of the rhesus retina. Oxytocin mRNA and protein were expressed in the human and rhesus RPE. Oxytocin mRNA and protein expression were observed in cultured hfRPE cells, and exposure of these cells to 100 nM OXT induced a transient 79 ± 1.5 nM increase of [Ca(2+)]i. Conclusions Oxytocin and OXTR are present in the posterior retina, and OXT induces an increase in hfRPE [Ca(2+)]i. These results suggest that the OXT-OXTR signaling pathway is active in the retina. We propose that OXT activation of the OXTR occurs in the posterior retina and that this may serve as a paracrine signaling pathway that contributes to communication between the cone photoreceptor and the RPE.

Competency-based medical education is gaining traction as a solution to address the challenges associated with the current time-based models of physician training. Competency-based medical education is an outcomes-based approach that involves identifying the abilities required of physicians and then designing the curriculum to support the achievement and assessment of these competencies. This paradigm defies the assumption that competence is achieved based on time spent on rotations and instead requires residents to demonstrate competence. The Royal College of Physicians and Surgeons of Canada (RCPSC) has launched Competence by Design (CBD), a competency-based approach for residency training and specialty practice. The first residents to be trained within this model will be those in medical oncology and otolaryngology-head and neck surgery in July, 2016. However, with approval from the RCPSC, the Department of Anesthesiology, University of Ottawa, launched an innovative competency-based residency training program July 1, 2015. The purpose of this paper is to provide an overview of the program and offer a blueprint for other programs planning similar curricular reform. The program is structured according to the RCPSC CBD stages and addresses all CanMEDS roles. While our program retains some aspects of the traditional design, we have made many transformational changes.

We have designed a mobile device application (RRate), to provide an efficient measurement of respiratory rate with clinically acceptable accuracy. The method is based on analysis of multiple consecutive breath intervals. We investigated in this study the difference in measurement variability between breaths as a representative of recording quality. Respiratory rate of 322 children aged 0 - 12 years at a Ugandan rural health centre were recorded using the RRate mobile application, and compared to respiratory rate recordings obtained from 22 volunteers using the RRate application while observing 10 videos of children breathing in a lab setting. The variability of the recorded breaths (confidence) of both groups follow a similar Weibull distribution. However, we observed a trend towards higher variability in the data obtained in the field (median 89.7% confidence) compared to the data obtained in the laboratory setting (median 92.6% confidence). This suggests that it is more difficult to obtain consistent measurements when assessing patients in a clinical setting, and therefore the confidence in the measured respiratory rate is reduced. The mobile device application provided a respiratory rate value up to 6 times faster than the current practice of one minute counting. The measure of variability between individual measured breaths provided a powerful way to display confidence in a measurement.

Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting.To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n = 21) or autologous (n = 15) SCT at our institution between 1982 and 2004. Pathologic classification included: lymphoblastic lymphoma (n = 12), Burkitt lymphoma (BL) (n = 5), diffuse large B-cell lymphoma (n = 4), anaplastic large cell lymphoma (ALCL) (n = 13), peripheral T cell lymphoma (n = 1), and undifferentiated NHL (n = 1). Donor source for allogeneic-SCT recipients was an HLA-matched related donor (n = 15), a matched unrelated donor (n = 4), or a mismatched donor (related n = 1; unrelated n = 1). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR).Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-SCT (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 61%, compared with 25% among patients with relapsed/refractory disease (P = 0.019).Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease.

The crystal structure of the highly specific γ-d-glutamyl-l-diamino acid endopeptidase YkfC from Bacillus cereus in complex with l-Ala-γ-d-Glu reveals the structural basis for the substrate specificity of NlpC/P60-family cysteine peptidases., Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-d-glutamyl-l-­diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (l-Ala-γ-d-Glu) enabled the identification of conserved sequence and structural signatures for recognition of l-Ala and γ-d-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial l-­alanine-γ-d-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site.

The crystal structure of the BVU2987 gene product from B. vulgatus (UniProt A6L4L1) reveals that members of the new Pfam family PF11396 (domain of unknown function; DUF2874) are similar to β-lactamase inhibitor protein and YpmB., Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a β-lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to β-lactamase inhibitor protein, PepSY and SmpA_OmlA proteins and hence are likely to function as inhibitory proteins.

Antithymocyte globulin (ATG) has been used in allogeneic stem-cell transplantation to prevent graft rejection and graft-versus-host disease (GvHD). Its use, however, has been associated with delayed T-cell reconstitution and prolonged susceptibility to opportunistic infections (OIs) especially in patients undergoing T cell–depleted (TCD) transplantation. Recently, a prospective trial was conducted in 52 adult patients (median age, 47 years) with various hematologic malignancies undergoing TCD transplantation from HLA-matched related donors without the use of ATG. The cytoreductive regimen consisted of hyperfractionated total body irradiation (HFTBI), thiotepa, and fludarabine. The preferred source of the graft was peripheral blood stem cells (PBSCs). No additional graft rejection or GvHD prophylaxis was given. All evaluable patients engrafted without any immune-mediated graft rejections. Disease-free survival (DFS) at 3 years was 61% in all patients, and 70% in patients with standard-risk disease. Acute GvHD was limited to grade 2 in 8% and chronic GvHD in 9% of patients. Life-threatening OIs occurred in 3 of 52 patients and was fatal in 1. This study demonstrates durable engraftment with a low incidence of GvHD despite the lack of ATG, as well as the curative potential of this regimen.