Analysis of guideline recommendations for treatment of asthma exacerbations in children: a Pediatric Emergency Research Networks (PERN) study.

RATIONALE: There is significant practice variation in acute paediatric asthma, particularly severe exacerbations. It is unknown whether this is due to differences in clinical guidelines. OBJECTIVES: To describe and compare the content and quality of clinical guidelines for the management of acute exacerbations of asthma in children between geographic regions. METHODS: Observational study of guidelines for the management of acute paediatric asthma from institutions across a global collaboration of six regional paediatric emergency research networks. MEASUREMENTS AND MAIN RESULTS: 158 guidelines were identified. Half provided recommendations for at least two age groups, and most guidelines provided treatment recommendations according to asthma severity.There were consistent recommendations for the use of inhaled short-acting beta-agonists and systemic corticosteroids. Inhaled anticholinergic therapy was recommended in most guidelines for severe and critical asthma, but there were inconsistent recommendations for its use in mild and moderate exacerbations. Other inhaled therapies such as helium-oxygen mixture (Heliox) and nebulised magnesium were inconsistently recommended for severe and critical illness.Parenteral bronchodilator therapy and epinephrine were mostly reserved for severe and critical asthma, with intravenous magnesium most recommended. There were regional differences in the use of other parenteral bronchodilators, particularly aminophylline.Guideline quality assessment identified high ratings for clarity of presentation, scope and purpose, but low ratings for stakeholder involvement, rigour of development, applicability and editorial independence. CONCLUSIONS: Current guidelines for the management of acute paediatric asthma exacerbations have substantial deficits in important quality domains and provide limited and inconsistent guidance for severe exacerbations.

Management and Outcomes of Wilms Tumor With Suprarenal Intravascular Extension: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: The purpose of this study was to describe management and outcomes from a contemporary cohort of children with Wilms tumor complicated by inferior vena caval thrombus. BACKGROUND: The largest series of these patients was published almost 2 decades ago. Since then, neoadjuvant chemotherapy has been commonly used to manage these patients, and outcomes have not been reported. METHODS: Retrospective review of 19 North American centers between 2009 and 2019. Patient and disease characteristics, management, and outcomes were investigated and analyzed. RESULTS: Of 124 patients, 81% had favorable histology (FH), and 52% were stage IV. IVC thrombus level was infrahepatic in 53 (43%), intrahepatic in 32 (26%), suprahepatic in 14 (11%), and cardiac in 24 (19%). Neoadjuvant chemotherapy using a 3-drug regimen was administered in 82% and postresection radiation in 90%. Thrombus level regression was 45% overall, with suprahepatic level showing the best response (62%). Cardiopulmonary bypass (CPB) was potentially avoided in 67%. The perioperative complication rate was significantly lower after neoadjuvant chemotherapy [(25%) vs upfront surgery (55%); P =0.005]. CPB was not associated with higher complications [CPB (50%) vs no CPB (27%); P =0.08]. Two-year event-free survival was 93% and overall survival was 96%, higher in FH cases (FH 98% vs unfavorable histology/anaplastic 82%; P =0.73). Neither incomplete resection nor viable thrombus cells affected event-free survival or overall survival. CONCLUSIONS: Multimodal therapy resulted in excellent outcomes, even with advanced-stage disease and cardiac extension. Neoadjuvant chemotherapy decreased the need for CPB to facilitate resection. Complete thrombectomy may not always be necessary.

International perspective on research priorities and outcome measures of importance in the care of children with acute exacerbations of asthma: a qualitative interview study.

BACKGROUND: Acute exacerbations of asthma are common in children, however, treatment decisions for severe exacerbations are challenging due to a lack of robust evidence. In order to create more robust research, a core set of outcome measures needs to be developed. In developing these outcomes, it is important to understand the views of clinicians who care for these children in particular, views that relate to outcome measures and research priorities. METHODS: To determine the views of clinicians, a total of 26 semistructured interviews based on the theoretical domains framework were conducted. These included experienced clinicians from emergency, intensive care and inpatient paediatrics across 17 countries. The interviews were recorded, and later transcribed. All data analyses were conducted in Nvivo by using thematic analysis. RESULTS: The length of stay in hospital and patient-focused parameters, such as timing to return to school and normal activity, were the most frequently highlighted outcome measures, with clinicians identifying the need to achieve a consensus on key core outcome measure sets. Most research questions focused on understanding the best treatment options, including the role of novel therapies and respiratory support. CONCLUSION: Our study provides an insight into what research questions and outcome measures clinicians view as important. In addition, information on how clinicians define asthma severity and measure treatment success will assist with methodological design in future trials. The current findings will be used in parallel with a further Paediatric Emergency Research Network study focusing on the child and family perspectives and will contribute to develop a core outcome set for future research.

Understanding the Balance of Entropy and Enthalpy in Hydrogen-Halide Noncovalent Bonding.

Hydrogen bonds are of great scientific interest, determining the free energy landscape and hence chemical and physical properties of many materials systems, for example, the hybrid organic-inorganic perovskites. Although these interactions are critical, understanding them is difficult in complex, multicomponent systems; hydrogen halides are ideal as simple binary model compounds for understanding the role of hydrogen bonding in physical properties like phase transitions. Here we investigate the orthorhombic low-temperature phase and the cubic high-temperature phase in HX (X = F, Cl, Br, or I) systems to understand how different hydrogen-halide bonds influence free energy profiles. We show that hydrogen fluoride has a qualitatively different behavior due to strong hydrogen bonding and hence a very different vibrational entropy. Heavier halides are in contrast rather similar in their physical properties; however, dispersion interactions play a more crucial role in these. These results have implications for the rational design of materials with hydrogen-halide bonds and tuning material properties in systems like mixed anion CH3NH3PbX3 perovskites.

Delivery practices and care experience during implementation of an adapted safe childbirth checklist and respectful care program in Chiapas, Mexico.

OBJECTIVE: To evaluate changes in quality of care after implementing an adapted safe childbirth checklist (SCC) in Chiapas, Mexico. METHODS: A convergent mixed-methods study was conducted among 447 women in labor who attended a rural community hospital between September 1, 2016, and June 30, 2017. Logistic regression analysis was used to evaluate adherence to evidence-based practices over time, adjusting for provider. Participants were surveyed about their perceptions of care after hospital discharge. A purposefully sampled subgroup also completed in-depth interviews. Thematic analysis was performed to evaluate perceptions of care. RESULTS: 384 (85.9%) women were attended by staff that used the adapted SCC during delivery. Of these, 221 and 28 completed the hospital discharge survey and in-depth interview, respectively. Adherence with offering a birth companion (odds ratio [OR] 3.06, 95% CI 1.40-6.68), free choice of birth position (2.75, 1.21-6.26), and immediate skin-to-skin contact (4.53, 1.97-10.39) improved 6-8 months after implementation. Participants' perceived quality of care improved over time. Provider communication generated positive perceptions. Reprimanding women for arriving in early labor or complaining of pain generated negative perceptions. CONCLUSION: Use of the adapted SCC improved quality of care through increased adherence with essential and respectful delivery practices.

Patient-reported outcomes following surgery for degenerative spondylolitshtesis: comparison of a universal and multitier health care system.

STUDY DESIGN: Retrospective review of results from a prospectively collected Canadian cohort in comparison to published literature. OBJECTIVES: (1) To investigate whether patients in a universal health care system have different outcomes than those in a multitier health care system in surgical management of degenerative spondylolisthesis (DS). (2) To identify independent factors predictive of outcome in surgical DS patients. SUMMARY OF BACKGROUND DATA: Canada has a national health insurance program with unique properties. It is a single-payer system, coverage is universal, and access to specialist care requires referral by the primary care physician. The United States on the other hand is a multitier public/private payer system with more rapid access for insured patients to specialist care. METHODS: Surgical DS patients treated between 2013 and 2016 in Canada were identified through the Canadian Spine Outcome Research Network (CSORN) database, a national registry that prospectively enrolls consecutive patients with spinal pathology from 16 tertiary care academic hospitals. This population was compared with the surgical DS arm of patients treated in the Spine Patients Outcome Research Trial (SPORT) study. We compared baseline demographics, spine-related, and health-related quality of life (HRQOL) outcomes at 3 months and 1 year. Multivariate analysis was used to identify factors predictive of outcome in surgical DS patients. RESULTS: The CSORN cohort of 213 patients was compared with the SPORT cohort of 248 patients. Patients in the CSORN cohort were younger (mean age 60.1 vs. 65.2; p<.001), comprised fewer females (60.1% vs. 67.7%; p=.09), and had a higher proportion of smokers (23.3% vs. 8.9%; p<.001). The SPORT cohort had more patients receiving compensation (14.6% vs. 7.7%; p<.001). The CSORN cohort consisted of patients with slightly greater baseline disability (Oswestry disability index scores: 47.7 vs. 44.0; p=.008) and had more patients with symptom duration of greater than 6 months (93.7% vs. 62.1%; p<.001). The CSORN cohort showed greater satisfaction with surgical results at 3 months (91.1% vs. 66.1% somewhat or very satisfied; p<.01) and 1 year (88.2% vs. 71.0%, p<.01). Improvements in back and leg pain were similar comparing the two cohorts. On multivariate analysis, duration of symptoms, treatment group (CSORN vs. SPORT) or insurance type (public/Medicare/Medicaid vs. Private/Employer) predicted higher level of postoperative satisfaction. Baseline depression was also associated with worse Oswestry disability index at 1-year postoperative follow-up in both cohorts. CONCLUSIONS: Surgical DS patients treated in Canada (CSORN cohort) reported higher levels of satisfaction than those treated in the United States (SPORT cohort) despite similar to slightly worse baseline HRQOL measures. Symptom duration and insurance type appeared to impact satisfaction levels. Improvements in other patient-reported health-related quality of life measures were similar between the cohorts.

Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury.

Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

Putting translational science on to a global stage.

Global collaboration in translational science promises to accelerate the discovery, development and dissemination of new medical interventions. Here, we introduce a new international collaboration of translational science organizations and highlight our initial strategy to reduce or remove bottlenecks in translation.

Automated analysis of retinal imaging using machine learning techniques for computer vision.

There are almost two million people in the United Kingdom living with sight loss, including around 360,000 people who are registered as blind or partially sighted. Sight threatening diseases, such as diabetic retinopathy and age related macular degeneration have contributed to the 40% increase in outpatient attendances in the last decade but are amenable to early detection and monitoring. With early and appropriate intervention, blindness may be prevented in many cases. Ophthalmic imaging provides a way to diagnose and objectively assess the progression of a number of pathologies including neovascular ("wet") age-related macular degeneration (wet AMD) and diabetic retinopathy. Two methods of imaging are commonly used: digital photographs of the fundus (the 'back' of the eye) and Optical Coherence Tomography (OCT, a modality that uses light waves in a similar way to how ultrasound uses sound waves). Changes in population demographics and expectations and the changing pattern of chronic diseases creates a rising demand for such imaging. Meanwhile, interrogation of such images is time consuming, costly, and prone to human error. The application of novel analysis methods may provide a solution to these challenges. This research will focus on applying novel machine learning algorithms to automatic analysis of both digital fundus photographs and OCT in Moorfields Eye Hospital NHS Foundation Trust patients. Through analysis of the images used in ophthalmology, along with relevant clinical and demographic information, DeepMind Health will investigate the feasibility of automated grading of digital fundus photographs and OCT and provide novel quantitative measures for specific disease features and for monitoring the therapeutic success.

A simplified approach for the simultaneous qualification of bioanalytical methods for multiple species at late discovery stage.

BACKGROUND: Although not required to be GLP compliant, the bioanalytical methods intended to be used in supporting pharmacokinetic and exploratory toxicokinetic characterization of compounds in late drug-discovery stage are highly desirable to be qualified with respect to accuracy, precision, matrix effects and selectivity, as well as various stability assessments. Since the method qualification for each species is typically conducted separately, it is often resource-intensive and time-consuming. RESULTS: In this work, we report a simplified approach to perform a non-GLP, multiple-species, bioanalytical-method qualification. In this approach, QC samples prepared from multiple species were quantified against standard curves from a single species. More importantly, multiple stability assessments were combined to produce combination stability QC samples under the assumption that if the combination stability QC samples met the acceptance criteria, so did each individual stability assessment. CONCLUSION: Using this simplified approach, a method qualification was typically completed in less than 2 weeks compared with the 5-8 weeks of a conventional method qualification. This approach was found to be useful for bioanalytical methods developed for both plasma and whole blood matrices.

Association of QRS duration and survival in dogs with dilated cardiomyopathy: a retrospective study of 266 clinical cases.

OBJECTIVE: The purpose of this study was to investigate the prognostic value of QRS duration in dogs with dilated cardiomyopathy (DCM) by studying its relationship with survival time. METHODS: The medical records of dogs diagnosed with DCM were retrospectively searched for good quality ECG tracings. The QRS duration was measured from the ECG tracing and two different models were used: binary variable (dogs were divided into 2 groups based on a QRS duration of <60 ms or ≥60 ms) and continuous variable. The survival times were analysed by the Kaplan-Meier method and Cox's proportional hazard model. RESULTS: 266 dogs met the inclusion and exclusion criteria. A QRS duration ≥60 ms was associated with a reduced survival time compared to those with a QRS duration <60 ms (Hazard Ratio of 1.34, 95% CI 1.05-1.71, P = 0.02). When considered as a continuous variable the Hazard Ratio was 1.015 for each increase in QRS duration of 1 ms (95% CI 1.006-1.024, p = 0.001).Dogs with a QRS duration < 60 ms had a median survival time (IQ range) of 25 weeks (97-65) and dogs with a QRS duration ≥60 ms had a median survival time (IQ range) of 13 weeks (3-34). CONCLUSION: The measurement of QRS duration is relatively simple to perform from a surface ECG recording. A duration ≥60 ms is associated with shorter survival times in dogs with DCM, which may provide practitioners with additional prognostic information.

Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.

Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2. These efforts led to the discovery of AMG 853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), which is being evaluated in human clinical trials for asthma.

A summary of some experimental data on LNG safety.

In a recent paper, Luketa-Hanlin reviewed the information in the public domain related to LNG safety. The purpose of this paper is to supplement that work by providing a summary of the experimental information that Advantica has collected on LNG behaviour over the course of the last 30 years. This summary includes previously unpublished information obtained as a result of a number of collaborative projects. Subjective comments are also made on the status of modelling for each of the topic areas and, in a discussion, views are provided on those areas where there are currently gaps that may have a major impact on evaluating the individual or societal risks associated with LNG operations.

Digital video.

The process of digital capture, editing, and archiving video has become an important aspect of documenting arthroscopic surgery. Recording the arthroscopic findings before and after surgery is an essential part of the patient's medical record. The hardware and software has become more reasonable to purchase, but the learning curve to master the software is steep. Digital video is captured at the time of arthroscopy to a hard disk, and written to a CD at the end of the operative procedure. The process of obtaining video of open procedures is more complex. Outside video of the procedure is recorded on digital tape with a digital video camera. The camera must be plugged into a computer to capture the video on the hard disk. Adobe Premiere software is used to edit the video and render the finished video to the hard drive. This finished video is burned onto a CD. We outline the choice of computer hardware and software for the manipulation of digital video. The techniques of backup and archiving the completed projects and files also are outlined. The uses of digital video for education and the formats that can be used in PowerPoint presentations are discussed.

Anterior occiput-to-axis screw fixation: part I: a case report, description of a new technique, and anatomical feasibility analysis.

STUDY DESIGN: A case report of anterior screw fixation from the axis to the occiput is described, as is the surgical technique. The pertinent anatomy is described with a radiographic assessment of the feasibility, safety, and general applicability of this technique. OBJECTIVES: To describe a novel technique of anterior occipitocervical fixation and the pertinent anatomy. SUMMARY OF BACKGROUND DATA: In unique clinical situations where posterior fixation techniques may not be possible or may have already failed, an anterior screw fixation technique may add stability to further attempts at obtaining a posterior arthrodesis. METHODS: A case report is presented, followed by a detailed description of the surgical technique. Ten normal cervical spines had radiographs and computed tomography scans with reformats reviewed to determine screw entry points, target points, and proposed screw trajectories. Following screw insertion in eight fresh frozen human cadaver spine specimens, dissection verified screw location relative to structures at risk. RESULTS: The ideal entry point is located caudal to the C2 superior facet joint in line with the medial third of the C2 superior facet. The screw is directed 25 degrees posteriorly in the sagittal plane and 15 degrees laterally in the coronal plane. The screw tip is located in the posterolateral third of the occipital condyle. Anatomic variation is considerable and makes this technique inadvisable in up to 20% of cases. Structures at risk include the vertebral artery and the hypoglossal nerve. CONCLUSIONS: This new technique of anterior fixation of the atlas to the occiput is feasible and safe if meticulous surgical planning is performed.

Catheter closure of patent ductus arteriosus in dogs: variation in ductal size requires different techniques.

BACKGROUND: : Catheter closure of patent ductus arteriosus Botalli (PDA) is increasingly replacing traditional surgical ligation via thoracotomy. A variety of techniques have been described in dogs, although the technique and implant chosen may depend on the minimum ductus diameter. OBJECTIVES: : To evaluate the feasibility and treatment of choice of catheter closure of large and small PDAs in dogs. METHODS: : In 16 dogs with a PDA, catheter closure was performed using transarterial embolisation using detachable or free coils, or transvenously using an Amplatzer, duct occluder (ADO). RESULTS: : In 8 dogs, closure of PDA with a minimum diameter of < 4 mm was achieved using detachable coils; 2 or more coils were required in 3 dogs. In 5 dogs with minimum ductus diameters of > 4 mm, detachable coils were not applicable. In one of these dogs, (incomplete) surgical ligation was performed and later a free coil placed for complete closure. In 2 dogs with moderately large PDA (5 mm), several free coils were implanted. Complete closure was not achieved in either dog and transient haemolysis occurred as a complication. In 2 dogs with a very large PDA (6 mm), implanted free coils embolised to pulmonary arteries and closure was then achieved using an ADO. In 3 dogs with an excessively large PDA (7.5-10 mm) closure was successfully achieved using an ADO with no complications. CONCLUSIONS: : Coil embolisation is readily feasible for closure of PDA < 4 mm, less feasible for PDA < 5 mm and unlikely to be feasible to close PDA > 5 mm. Detachable coils are safe for PDA < 4 mm, and the ADO is an excellent device for PDA > 5 mm.