Accelerating pediatric Hodgkin lymphoma research: the Hodgkin Lymphoma Data Collaboration (NODAL).

Data commons have proven to be an indispensable avenue for advancing pediatric cancer research by serving as unified information technology platforms that, when coupled with data standards, facilitate data sharing. The Pediatric Cancer Data Commons, the flagship project of Data for the Common Good (D4CG), collaborates with disease-based consortia to facilitate development of clinical data standards, harmonization and pooling of clinical data from disparate sources, establishment of governance structure, and sharing of clinical data. In the interest of international collaboration, researchers developed the Hodgkin Lymphoma Data Collaboration and forged a relationship with the Pediatric Cancer Data Commons to establish a data commons for pediatric Hodgkin lymphoma. Herein, we describe the progress made in the formation of Hodgkin Lymphoma Data Collaboration and foundational goals to advance pediatric Hodgkin lymphoma research.

Comparison of 2 Robotic Systems for Pediatric Stereoelectroencephalography Implantation.

BACKGROUND: Stereoelectroencephalography (SEEG) remains critical in guiding epilepsy surgery. Robot-assisted techniques have shown promise in improving SEEG implantation outcomes but have not been directly compared. In this single-institution series, we compared ROSA and Stealth AutoGuide robots in pediatric SEEG implantation. METHODS: We retrospectively reviewed 21 sequential pediatric SEEG implantations consisting of 6 ROSA and 15 AutoGuide procedures. We determined mean operative time, time per electrode, root mean square (RMS) registration error, and surgical complications. Three-dimensional radial distances were calculated between each electrode's measured entry and target points with respective errors from the planned trajectory line. RESULTS: Mean overall/per electrode operating time was 73.5/7.5 minutes for ROSA and 126.1/10.9 minutes for AutoGuide (P = 0.030 overall, P = 0.082 per electrode). Mean RMS registration error was 0.77 mm (0.55-0.93 mm) for ROSA and 0.6 mm (0.2-1.0 mm) for AutoGuide (P = 0.26). No procedures experienced complications. The mean radial (entry point error was 1.23 ± 0.11 mm for ROSA and 2.65 ± 0.12 mm for AutoGuide (P < 0.001), while the mean radial target point error was 1.86 ± 0.15 mm for ROSA and 3.25 ± 0.16 mm for AutoGuide (P < 0.001). CONCLUSIONS: Overall operative time was greater for AutoGuide procedures, although there was no statistically significant difference in time per electrode. Both systems are highly accurate with no significant RMS error difference. While the ROSA robot yielded significantly lower entry and target point errors, both robots are safe and reliable for deep electrode insertion in pediatric epilepsy.

Using A Standardized Nomenclature to Semantically Map Oncology-Related Concepts from Common Data Models to a Pediatric Cancer Data Model.

The Pediatric Cancer Data Commons (PCDC) comprises an international community whose ironclad commitment to data sharing is combatting pediatric cancer in an unprecedented way. The byproduct of their data sharing efforts is a gold-standard consensus data model covering many types of pediatric cancer. This article describes an effort to utilize SSSOM, an emerging specification for semantically-rich data mappings, to provide a "hub and spoke" model of mappings from several common data models (CDMs) to the PCDC data model. This provides important contributions to the research community, including: 1) a clear view of the current coverage of these CDMs in the domain of pediatric oncology, and 2) a demonstration of creating standardized mappings. These mappings can allow downstream crosswalk for data transformation and enhance data sharing. This can guide those who currently create and maintain brittle ad hoc data mappings in order to utilize the growing volume of viable research data.

International perspective on integrated care models in child and adult mental health.

The dearth of child and adolescent mental health services (CAMHS) is a global problem. Integrating CAMHS in primary care has been offered as a solution. We sampled integrated care perspectives from colleagues around the world. Our findings include various models of integrated care namely: the stepped care model in Australia; shared care in the United Kingdom (UK) and Spain; school-based collaborative care in Qatar, Singapore and the state of Texas in the US; collaborative care in Canada, Brazil, US, and Uruguay; coordinated care in the US; and, developing collaborative care models in low-resource settings, like Kenya and Micronesia. These findings provide insights into training initiatives necessary to build CAMHS workforce capacity using integrated care models, each with the ultimate goal of improving access to care. Despite variations and progress in implementing integrated care models internationally, common challenges exist: funding within complex healthcare systems, limited training mechanisms, and geopolitical/policy issues. Supportive healthcare policy, robust training initiatives, ongoing quality improvement and measurement of outcomes across programs would provide data-driven support for the expansion of integrated care and ensure its sustainability.

Complete corpus callosotomy using a frameless navigation probe through a minicraniotomy in children with medically refractory epilepsy: A case series and technical note.

Background: Medically refractory epilepsy constitutes up to one-third of the epilepsy pediatric patients. Corpus callosotomy (CC) has been used for the treatment of medically refractory epilepsy in children with atonic seizures and generalized tonic-clonic (GTC) seizures. In this case series study, we are describing a novel technique for CC using the frameless navigation probe through a minicraniotomy. Methods: Thirteen pediatric patients with the diagnosis of medically refractory epilepsy predominantly GTC with drop attack who underwent extensive Phase I. An L-shape was done, then through a 4 × 3 cm craniotomy, we were able to open the interhemispheric fissure until the corpus callosum is visualized. The Stealth probe is then used to go down to the midline raphe which is followed anteriorly then traced posteriorly to the anterior border of the vein of Galen. Finally, the Stealth probe is used to confirm the completeness of the callosotomy. Results: The procedure was accomplished successfully with no intraoperative complications; mean surgical time is 3 h:07 m. The mean follow-up was 31.5 months. All patients achieved significant seizure control. No patients experienced worsening of their atonic seizures after surgery compared with their preoperative state; however, six patients achieved Engel Class I, four patients achieved Engel Class II, and three patients achieved Engel Class III. Conclusion: Complete CC using a frameless navigation probe is a novel and effective technique for the treatment of medically refractory epilepsy with a very good surgical and seizure outcomes, minimal neurological morbidity, minimal blood loss, and short OR time.

LocalVar: a local variant collection manager to asynchronously detect synonyms, HGVS expression changes, and variant interpretation changes from ClinVar.

While there are several public repositories of biological sequence variation data and associated annotations, there is little open-source tooling designed specifically for the upkeep of local collections of variant data. Many clinics curate and maintain such local collections and are burdened by frequent changes in the representation of those variants and evolving interpretations of clinical significance. A dictionary of genetic variants from the Huntsman Cancer Institute was analyzed over a period of two years and used to inform the development of LocalVar. This tool uses publicly available ClinVar files to provide the following functionality: auto-complete search bar to pre-empt duplicate entries; single or bulk new variant record entry; auto-detection of duplicate and synonymous variant records; asynchronous suggestion of HGVS expression or variant interpretation updates; extensive edit history tracking; and the easy export of the collection (.csv), edit history (.json), or HGVS synonym bins (.json).

ResultsMyWay: combining Fast Healthcare Interoperability Resources (FHIR), Clinical Quality Language (CQL), and informational resources to create a newborn screening application.

Newborn screening (NBS) can be life-changing for the families of infants who test positive for a rare condition. While resources exist to support these families, there can be delays in sharing these resources due to communication lag between the laboratory, result interpreting clinician, family of the newborn, and additional care providers. This delay can also be exacerbated when additional health history is required from the mother and infant. ResultsMyWay is a proof-of-concept application that uses Clinical Quality Language (CQL) to automate the search for this additional health history. It also translates the NBS results into Fast Healthcare Interoperability Resources (FHIR), increasing both the ease of exchange and the future utility of these data points. After the families are given the NBS results, ResultsMyWay then acts as a hub for several types of informational resources about the recently diagnosed condition.

A comparison of machine learning classifiers for pediatric epilepsy using resting-state functional MRI latency data.

Epilepsy affects 1 in 150 children under the age of 10 and is the most common chronic pediatric neurological condition; poor seizure control can irreversibly disrupt normal brain development. The present study compared the ability of different machine learning algorithms trained with resting-state functional MRI (rfMRI) latency data to detect epilepsy. Preoperative rfMRI and anatomical MRI scans were obtained for 63 patients with epilepsy and 259 healthy controls. The normal distribution of latency z-scores from the epilepsy and healthy control cohorts were analyzed for overlap in 36 seed regions. In these seed regions, overlap between the study cohorts ranged from 0.44-0.58. Machine learning features were extracted from latency z-score maps using principal component analysis. Extreme Gradient Boosting (XGBoost), Support Vector Machines (SVM), and Random Forest algorithms were trained with these features. Area under the receiver operating characteristics curve (AUC), accuracy, sensitivity, specificity and F1-scores were used to evaluate model performance. The XGBoost model outperformed all other models with a test AUC of 0.79, accuracy of 74%, specificity of 73%, and a sensitivity of 77%. The Random Forest model performed comparably to XGBoost across multiple metrics, but it had a test sensitivity of 31%. The SVM model did not perform >70% in any of the test metrics. The XGBoost model had the highest sensitivity and accuracy for the detection of epilepsy. Development of machine learning algorithms trained with rfMRI latency data could provide an adjunctive method for the diagnosis and evaluation of epilepsy with the goal of enabling timely and appropriate care for patients.

Indications for Inpatient Magnetoencephalography in Children - An Institution's Experience.

Magnetoencephalography (MEG) is recognized as a valuable non-invasive clinical method for localization of the epileptogenic zone and critical functional areas, as part of a pre-surgical evaluation for patients with pharmaco-resistant epilepsy. MEG is also useful in localizing functional areas as part of pre-surgical planning for tumor resection. MEG is usually performed in an outpatient setting, as one part of an evaluation that can include a variety of other testing modalities including 3-Tesla MRI and inpatient video-electroencephalography monitoring. In some clinical circumstances, however, completion of the MEG as an inpatient can provide crucial ictal or interictal localization data during an ongoing inpatient evaluation, in order to expedite medical or surgical planning. Despite well-established clinical indications for performing MEG in general, there are no current reports that discuss indications or considerations for completion of MEG on an inpatient basis. We conducted a retrospective institutional review of all pediatric MEGs performed between January 2012 and December 2020, and identified 34 cases where MEG was completed as an inpatient. We then reviewed all relevant medical records to determine clinical history, all associated diagnostic procedures, and subsequent treatment plans including epilepsy surgery and post-surgical outcomes. In doing so, we were able to identify five indications for completing the MEG on an inpatient basis: (1) super-refractory status epilepticus (SRSE), (2) intractable epilepsy with frequent electroclinical seizures, and/or frequent or repeated episodes of status epilepticus, (3) intractable epilepsy with infrequent epileptiform discharges on EEG or outpatient MEG, or other special circumstances necessitating inpatient monitoring for successful and safe MEG data acquisition, (4) MEG mapping of eloquent cortex or interictal spike localization in the setting of tumor resection or other urgent neurosurgical intervention, and (5) international or long-distance patients, where outpatient MEG is not possible or practical. MEG contributed to surgical decision-making in the majority of our cases (32 of 34). Our clinical experience suggests that MEG should be considered on an inpatient basis in certain clinical circumstances, where MEG data can provide essential information regarding the localization of epileptogenic activity or eloquent cortex, and be used to develop a treatment plan for surgical management of children with complicated or intractable epilepsy.

Convolutional Neural Networks for Pediatric Refractory Epilepsy Classification Using Resting-State Functional Magnetic Resonance Imaging.

OBJECTIVE: This study aims to evaluate the performance of convolutional neural networks (CNNs) trained with resting-state functional magnetic resonance imaging (rfMRI) latency data in the classification of patients with pediatric epilepsy from healthy controls. METHODS: Preoperative rfMRI and anatomic magnetic resonance imaging scans were obtained from 63 pediatric patients with refractory epilepsy and 259 pediatric healthy controls. Latency maps of the temporal difference between rfMRI and the global mean signal were calculated using voxel-wise cross-covariance. Healthy control and epilepsy latency z score maps were pseudorandomized and partitioned into training data (60%), validation data (20%), and test data (20%). Healthy control individuals and patients with epilepsy were labeled as negative and positive, respectively. CNN models were then trained with the designated training data. Model hyperparameters were evaluated with a grid-search method. The model with the highest sensitivity was evaluated using unseen test data. Accuracy, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve were used to evaluate the ability of the model to classify epilepsy in the test data set. RESULTS: The model with the highest validation sensitivity correctly classified 74% of unseen test patients with 85% sensitivity, 71% specificity, F1 score of 0.56, and an area under the receiver operating characteristic curve of 0.86. CONCLUSIONS: Using rfMRI latency data, we trained a CNN model to classify patients with pediatric epilepsy from healthy controls with good performance. CNN could serve as an adjunct in the diagnosis of pediatric epilepsy. Identification of pediatric epilepsy earlier in the disease course could decrease time to referral to specialized epilepsy centers and thus improve prognosis in this population.

Effect of once-daily fluticasone furoate/vilanterol versus vilanterol alone on bone mineral density in patients with COPD: a randomized, controlled trial.

BACKGROUND: The relationship between inhaled corticosteroids and bone mineral density (BMD) remains uncertain despite extensive research. METHODS: This was an international, multicenter, randomized, double-blind, parallel-group, 3-year noninferiority study. Patients with chronic obstructive pulmonary disease (COPD) (⩾40 years of age; smoking history ⩾10 pack years) and at least one native hip evaluable for BMD were enrolled and randomized 1:1, stratified by sex, to treatment with vilanterol (VI) 25 µg or fluticasone furoate/vilanterol (FF/VI) 100 µg/25 µg. BMD measurements were taken via dual-energy X-ray absorptiometry every 6 months. The primary endpoint was assessment of the noninferiority of change from baseline in total hip BMD per year at the -1% noninferiority level. Change from baseline in BMD at the lumbar spine and BMD measurements by sex were secondary endpoints. Incidences of COPD exacerbations and bone fractures throughout the study were also recorded. RESULTS: Of 283 randomized patients, 170 (60%) completed the study. Noninferiority was demonstrated for FF/VI versus VI with regards to change from baseline in total hip BMD per year, with changes of -0.27% and 0.18%, respectively, and a treatment difference of -0.46% per year [95% confidence interval (CI) -0.97 to 0.06]. The treatment difference for FF/VI versus VI regarding lumbar spine BMD was -0.51% per year (95% CI -1.11 to 0.10). COPD exacerbations and bone fracture rates were similar between treatment groups. CONCLUSION: FF/VI showed noninferiority to VI for change from baseline in total hip BMD per year, when assessed at the -1% noninferiority margin in a combined sample of men and women with COPD.The reviews of this paper are available via the supplemental material section.

Translating Social Determinants of Health into Standardized Clinical Entities.

Social determinants of health (SDH) are a valuable source of health information which still are not fully utilized in the clinical space. Knowing that a certain patient has trouble finding transportation, has a potentially hazardous relationship with a family member or close relative, is currently unemployed, or various other social factors would allow providers to tailor treatment plans in a way to best help that patient. However, these SDH must be gathered, represented, and stored in a standardized way before they can be leveraged by informatics tools designed for health providers. This process of translating SDH to standardized clinical entities includes two main steps. The first is a collaborative effort to establish an ontology of medical terminology codes (i.e., ICD, SNOMED, LOINC, etc.) which can be used to uniformly represent SDH as coded concepts. The second is a collaborative effort to use the FHIR standard to create profiles and extensions which will allow FHIR resources to be used to store the coded SDH as clinical entities. Each of these steps has their own complexities that must be considered and accounted for in future efforts to create interoperable clinical informatics solutions which utilize SDH.

FHIR Lab Reports: using SMART on FHIR and CDS Hooks to increase the clinical utility of pharmacogenomic laboratory test results.

Laboratory tests are a common aspect of clinical care and are the primary source of clinical genomic data. However, most laboratories use PDF documents to store and exchange the results of these tests. This locks the data into a static format and leaves the results only human-readable. The ordering clinician uses the results, but after that the information is unlikely to be used again. Future use would require a clinician to know that the test was performed, know where to find the PDF report, and take the time to open it and determine relevance to that future scenario. New computational standards such as SMART on FHIR and CDS Hooks present opportunities to better utilize these results, both physically upon receipt and asynchronously in future clinical encounters for that patient. Full app available at https://github.com/mwatkin8/FHIR-Lab-Reports-App. Demo available at http://hematite.genetics.utah.edu/FHIR-Lab-Reports/.

A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD.

BACKGROUND: Batefenterol (BAT) is a bi-functional molecule with both muscarinic antagonist and ß2-adrenoceptor agonist pharmacology. This Phase II, randomized, placebo-controlled, double-blind study evaluated the safety and tolerability of BAT 300 µg with fluticasone furoate (FF) 100 µg administered via the ELLIPTA inhaler (BAT/FF 300/100). METHODS: Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0-4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0-4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board. RESULTS: Sixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: - 2.2 beats per minute (bpm), 95% confidence interval [CI]: - 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0-4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred. CONCLUSIONS: Six weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02573870 (submitted October 12, 2015).

Universal patterns in passenger flight departure delays.

Departure delays are a major cause of economic loss and inefficiency in the growing industry of passenger flights. A departure delay of a current flight is inevitably affected by the late arrival of the flight immediately preceding it with the same aircraft. We seek to understand the mechanisms of such propagated delays, and to obtain universal metrics by which to evaluate an airline's operational effectiveness in delay alleviation. Here we use big data collected by the American Bureau of Transportation Statistics to design models of flight delays. Offering two dynamic models of delay propagation, we divided all carriers into two groups exhibiting a shifted power law or an exponentially truncated shifted power law delay distribution, revealing two universal delay propagation classes. Three model parameters, extracted directly from dual data mining, help characterize each airline's operational efficiency in delay mitigation. Therefore, our modeling framework provides the crucially lacking evaluation indicators for airlines, potentially contributing to the mitigation of future departure delays.

The impact of race on choice of location for elective surgical care in New York city.

BACKGROUND: The "white-flight" phenomenon of the mid-20th century contributed to the perpetuation of residential segregation in American society. In light of recent reports of racial segregation in our healthcare system, could a contemporary "white-flight" phenomenon also exist? METHODS: The New York Statewide Planning and Research Cooperative System was used to identify all Manhattan and Bronx residents of New York city who underwent elective cardiothoracic, colorectal, general, and vascular surgeries from 2010 to 2016. Primary outcome was borough of surgical care in relation to patient's home borough. Multivariable analyses were performed. RESULTS: White patients who reside in the Bronx are significantly more likely than racial minorities to travel into Manhattan for elective surgical care, and these differences persist across different insurance types, including Medicare. CONCLUSIONS: Marked race-based differences in choice of location for elective surgical care exist in New York city. If left unchecked, these differences can contribute to furthering racial segregation within our healthcare system.

Risk score for nonhome discharge after lower extremity bypass.

OBJECTIVE: Patients undergoing lower extremity bypass (LEB) for peripheral artery disease require intensive health care resource utilization including rehabilitation and skilled nursing facilities. However, few studies have evaluated factors that lead to nonhome discharge (NHD) in this population of patients. This study sought to predict NHD by preoperative risk factors in patients undergoing LEB for peripheral artery disease using a novel risk score. METHODS: The Vascular Study Group of New England database was queried for elective LEB for peripheral artery disease including claudication and critical limb ischemia from 2003 to 2017. Patients were excluded if the procedure was not elective, if they were not admitted from home, if they were bedridden, or if they died during the index admission. Only preoperative factors were considered in the analysis. The primary end point was NHD including rehabilitation and skilled nursing facilities. Data were split two-thirds for model derivation and one-third for validation. In the derivation cohort, bivariate analysis assessed the association of preoperative factors with NHD. A parsimonious manual stepwise binary logistic regression for NHD aimed at maximizing the C statistic while maintaining model simplicity was performed. A risk score was developed using the ß coefficients and applied to the validation data set. The risk score performance was assessed using a C statistic and Hosmer-Lemeshow test for model fit. RESULTS: There were 10,145 cases included with an overall NHD rate of 26.4% (n = 2676). Mean age was 66 years (range, 41-90 years). NHD patients were older (72 years vs 64 years; P < .01) and more frequently male (57.2% vs 42.8%; P < .01) and nonwhite (16.1% vs 9.9%; P < .01); they more frequently had tissue loss (54.2% vs 23.0%; P < .01), anemia (16.0% vs 5.3%; P < .01), severe cardiac comorbidity (21.8% vs 10.5%; P < .01), and insulin-dependent diabetes (33.3% vs 18.2%; P < .01). On multivariable analysis, factors associated with NHD included age, sex, nonwhite race, tissue loss, cardiac comorbidity, partial ambulatory deficit, and insulin-dependent diabetes. The C statistic was 0.78 in the derivation group and 0.79 in the validation group, with Hosmer-Lemeshow P > .999. The risk score ranged from 0 to 18, with a mean score of 4 (standard deviation ±3.5). The risk score was divided into low risk (0-4 points; n = 5272 [52%]; NHD = 10.1%]), moderate risk (5-9 points; n = 3663 [36.7%]; NHD = 36.7%), and high risk (≥10 points; n = 1210 [11.9%]; NHD = 66.1%). CONCLUSIONS: This novel risk score was highly predictive for NHD after LEB for peripheral artery disease using only preoperative comorbidities. High-risk patients account for 12% of LEB but nearly a third of all patients requiring NHD. This risk score can be used preoperatively to determine high-risk patients for NHD, which may help improve preoperative counseling and hospital efficiency by allocating resources appropriately.

Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial.

BACKGROUND: Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. METHODS: The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 µg once-daily, umeclidinium 62.5 µg once-daily or salmeterol 50 µg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. RESULTS: Change from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% [p < 0.01]) and salmeterol (by 26-41% [p < 0.001]). Safety profiles were similar between treatments. CONCLUSIONS: Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Contributions of GRACE to understanding climate change.

Time-resolved satellite gravimetry has revolutionized understanding of mass transport in the Earth system. Since 2002, the Gravity Recovery and Climate Experiment (GRACE) has enabled monitoring of the terrestrial water cycle, ice sheet and glacier mass balance, sea level change and ocean bottom pressure variations and understanding responses to changes in the global climate system. Initially a pioneering experiment of geodesy, the time-variable observations have matured into reliable mass transport products, allowing assessment and forecast of a number of important climate trends and improve service applications such as the U.S. Drought Monitor. With the successful launch of the GRACE Follow-On mission, a multi decadal record of mass variability in the Earth system is within reach.

Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD.

BACKGROUND: Batefenterol is a novel bifunctional muscarinic antagonist ß2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development. PATIENTS AND METHODS: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0-6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose-response modeling, respectively, on day 42. RESULTS: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed. CONCLUSION: Batefenterol 300 µg may represent the optimal dose for Phase III studies.