Absence of 3a0 charge density wave order in the infinite-layer nickelate NdNiO2.

A hallmark of many unconventional superconductors is the presence of many-body interactions that give rise to broken-symmetry states intertwined with superconductivity. Recent resonant soft X-ray scattering experiments report commensurate 3a0 charge density wave order in infinite-layer nickelates, which has important implications regarding the universal interplay between charge order and superconductivity in both cuprates and nickelates. Here we present X-ray scattering and spectroscopy measurements on a series of NdNiO2+x samples, which reveal that the signatures of charge density wave order are absent in fully reduced, single-phase NdNiO2. The 3a0 superlattice peak instead originates from a partially reduced impurity phase where excess apical oxygens form ordered rows with three-unit-cell periodicity. The absence of any observable charge density wave order in NdNiO2 highlights a crucial difference between the phase diagrams of cuprate and nickelate superconductors.

Treatment rates and healthcare costs of patients with fragility fracture by site of care: a real-world data analysis.

In a characterization of treatment rates and healthcare costs among patients with an osteoporotic-related fragility fracture overall and by site of care, costs were high and treatment rates were low. PURPOSE: Osteoporotic fractures can be debilitating, even fatal, among older adults. The cost of osteoporosis and related fractures is projected to increase to more than $25 billion by 2025. The objective of this analysis is to characterize disease-related treatment rates and healthcare costs of patients with an osteoporotic fragility fracture overall and by site of fracture diagnosis. METHODS: In this retrospective analysis, individuals with fragility fractures were identified in the Merative MarketScan® Commercial and Medicare Databases among women 50 years of age or older and diagnosed with fragility fracture between 1/1/2013 and 6/30/2018 (earliest fracture diagnosis = index). Cohorts were categorized by clinical site of care where the diagnosis of fragility fracture was made and were continuously followed for 12 months prior to and following index. Sites of care were inpatient admission, outpatient office, outpatient hospital, emergency room hospital, and urgent care. RESULTS: Of the 108,965 eligible patients with fragility fracture (mean age 68.8), most were diagnosed during an inpatient admission or outpatient office visit (42.7%, 31.9%). The mean annual healthcare costs among patients with fragility fracture were $44,311 (± $67,427) and were highest for those diagnosed in an inpatient setting ($71,561 ± $84,072). Compared with other sites of care at fracture diagnosis, patients diagnosed during an inpatient admission also had highest proportion of subsequent fractures (33.2%), osteoporosis diagnosis (27.7%), and osteoporosis therapy (17.2%) during follow-up. CONCLUSION: The site of care for diagnosis of fragility fracture affects treatment rates and healthcare costs. Further studies are needed to determine how attitude or knowledge about osteoporosis treatment or healthcare experiences differ at various clinical sites of care in the medical management of osteoporosis.

Establishment of local wastewater-based surveillance programmes in response to the spread and infection of COVID-19 - case studies from South Africa, the Netherlands, Turkey and England.

The COVID-19 pandemic has resulted in over 340 million infection cases (as of 21 January 2022) and more than 5.57 million deaths globally. In reaction, science, technology and innovation communities across the globe have organised themselves to contribute to national responses to COVID-19 disease. A significant contribution has been from the establishment of wastewater-based epidemiological (WBE) surveillance interventions and programmes for monitoring the spread of COVID-19 in at least 55 countries. Here, we examine and share experiences and lessons learnt in establishing such surveillance programmes. We use case studies to highlight testing methods and logistics considerations associated in scaling the implementing of such programmes in South Africa, the Netherlands, Turkey and England. The four countries were selected to represent different regions of the world and the perspective based on the considerable progress made in establishing and implementing their national WBE programmes. The selected countries also represent different climatic zones, economies, and development stages, which influence the implementation of national programmes of this nature and magnitude. In addition, the four countries' programmes offer good experiences and lessons learnt since they are systematic, and cover extensive areas, disseminate knowledge locally and internationally and partnered with authorities (government). The programmes also strengthened working relations and partnerships between and among local and global organisations. This paper shares these experiences and lessons to encourage others in the water and public health sectors on the benefits and value of WBE in tackling SARS-CoV-2 and related future circumstances.

The clinician's guide to prevention and treatment of osteoporosis.

Osteoporosis is the most common metabolic bone disease in the USA and the world. It is a subclinical condition until complicated by fracture(s). These fractures place an enormous medical and personal burden on individuals who suffer from them and take a significant economic toll. Any new fracture in an adult aged 50 years or older signifies imminent elevated risk for subsequent fractures, particularly in the year following the initial fracture. What a patient perceives as an unfortunate accident may be seen as a sentinel event indicative of bone fragility and increased future fracture risk even when the result of considerable trauma. Clinical or subclinical vertebral fractures, the most common type of osteoporotic fractures, are associated with a 5-fold increased risk for additional vertebral fractures and a 2- to 3-fold increased risk for fractures at other sites. Untreated osteoporosis can lead to a vicious cycle of recurrent fracture(s), often resulting in disability and premature death. In appropriate patients, treatment with effective antifracture medication prevents fractures and improves outcomes. Primary care providers and medical specialists are critical gatekeepers who can identify fractures and initiate proven osteoporosis interventions. Osteoporosis detection, diagnosis, and treatment should be routine practice in all adult healthcare settings. The Bone Health and Osteoporosis Foundation (BHOF) - formerly the National Osteoporosis Foundation - first published the Clinician's Guide in 1999 to provide accurate information on osteoporosis prevention and treatment. Since that time, significant improvements have been made in diagnostic technologies and treatments for osteoporosis. Despite these advances, a disturbing gap persists in patient care. At-risk patients are often not screened to establish fracture probability and not educated about fracture prevention. Most concerning, the majority of highest risk women and men who have a fracture(s) are not diagnosed and do not receive effective, FDA-approved therapies. Even those prescribed appropriate therapy are unlikely to take the medication as prescribed. The Clinician's Guide offers concise recommendations regarding prevention, risk assessment, diagnosis, and treatment of osteoporosis in postmenopausal women and men aged 50 years and older. It includes indications for bone densitometry as well as fracture risk thresholds for pharmacologic intervention. Current medications build bone and/or decrease bone breakdown and dramatically reduce incident fractures. All antifracture therapeutics treat but do not cure the disease. Skeletal deterioration resumes sooner or later when a medication is discontinued-sooner for nonbisphosphonates and later for bisphosphonates. Even if normal BMD is achieved, osteoporosis and elevated risk for fracture are still present. The diagnosis of osteoporosis persists even if subsequent DXA T-scores are above - 2.5. Ongoing monitoring and strategic interventions will be necessary if fractures are to be avoided. In addition to pharmacotherapy, adequate intake of calcium and vitamin D, avoidance of smoking and excessive alcohol intake, weight-bearing and resistance-training exercise, and fall prevention are included in the fracture prevention armamentarium. Where possible, recommendations in this guide are based on evidence from RCTs; however, relevant published data and guidance from expert clinical experience provides the basis for recommendations in those areas where RCT evidence is currently deficient or not applicable to the many osteoporosis patients not considered for RCT participation due to age and morbidity.

Post-fracture care programs for prevention of subsequent fragility fractures: a literature assessment of current trends.

Post-fracture care (PFC) programs evaluate and manage patients with a minimal trauma or fragility fracture to prevent subsequent fractures. We conducted a literature review to understand current trends in PFC publications, evaluate key characteristics of PFC programs, and assess their clinical effectiveness, geographic variations, and cost-effectiveness. We performed a search for peer-reviewed articles published between January 2003 and December 2020 listed in PubMed or Google Scholar. We categorized identified articles into 4 non-mutually exclusive PFC subtopics based on keywords and abstract content: PFC Types, PFC Effectiveness/Success, PFC Geography, and PFC Economics. The literature search identified 784 eligible articles. Most articles fit into multiple PFC subtopics (PFC Types, 597; PFC Effectiveness/Success, 579; PFC Geography, 255; and PFC Economics, 98). The number of publications describing how PFC programs can improve osteoporosis treatment rates has markedly increased since 2003; however, publication gaps remain, including low numbers of publications from some countries with reported high rates of osteoporosis and/or hip fractures. Fracture liaison services and geriatric/orthogeriatric services were the most common models of PFC programs, and both were shown to be cost-effective. We identified a need to expand and refine PFC programs and to standardize patient identification and reporting on quality improvement measures. Although there is an increasing awareness of the importance of PFC programs, publication gaps remain in most countries. Improvements in established PFC programs and implementation of new PFC programs are still needed to enhance equitable patient care to prevent occurrence of subsequent fractures.

Treatment patterns and long-term persistence with osteoporosis therapies in women with Medicare fee-for-service (FFS) coverage.

Osteoporosis, a chronic disease, requires long-term therapy. In Medicare-insured women, denosumab persistence was higher than oral bisphosphonate persistence over up to 3 years of follow-up. Longer-term persistence was higher among women who persisted in the first year of therapy. INTRODUCTION: Osteoporosis, a chronic, progressive disease, requires long-term therapy; this study assessed long-term persistence with anti-resorptive therapies in postmenopausal women. METHODS: This retrospective cohort study used administrative claims for women with data in the 100% Medicare osteoporosis sample who initiated (index date) denosumab, oral/intravenous (IV) bisphosphonate, or raloxifene between 2011 and 2014 and who had ≥ 1 year (zoledronic acid: 14 months) of pre-initiation medical/pharmacy coverage (baseline). Persistence was assessed from index date through end of continuous coverage, post-index evidence of censoring events (e.g., incident cancer), death, or end of study (December 31, 2015). RESULTS: The study included 318,419 oral bisphosphonate users (78% alendronate), 145,056 denosumab users, 48,066 IV bisphosphonate users, and 31,400 raloxifene users; mean age ranged from 75.5 years (raloxifene) to 78.5 years (denosumab). In women with at least 36 months of follow-up (denosumab N = 25,107; oral bisphosphonates N = 79,710), more denosumab than oral bisphosphonate initiators were persistent at 1 year (73% vs. 39%), 2 years (50% vs. 25%), and 3 years (38% vs. 17%). Persistence decreased over time for all treatment groups, with denosumab users having the highest persistence in every follow-up time interval at or after 18 months. Women using denosumab, oral bisphosphonates, or raloxifene who persisted in a given year were more likely to remain persistent through the subsequent year. CONCLUSIONS: Denosumab users persisted longer with therapy than women using other anti-resorptive medications, including oral bisphosphonates. Early persistence may predict long-term persistence. Overall persistence with osteoporosis medications is suboptimal and may impact fracture risk. Efforts to improve first year persistence are needed.

Femtosecond control of phonon dynamics near a magnetic order critical point.

The spin-phonon interaction in spin density wave (SDW) systems often determines the free energy landscape that drives the evolution of the system. When a passing energy flux, such as photoexcitation, drives a crystalline system far from equilibrium, the resulting lattice displacement generates transient vibrational states. Manipulating intermediate vibrational states in the vicinity of the critical point, where the SDW order parameter changes dramatically, would then allow dynamical control over functional properties. Here we combine double photoexcitation with an X-ray free-electron laser (XFEL) probe to control and detect the lifetime and magnitude of the intermediate vibrational state near the critical point of the SDW in chromium. We apply Landau theory to identify the mechanism of control as a repeated partial quench and sub picosecond recovery of the SDW. Our results showcase the capabilities to influence and monitor quantum states by combining multiple optical photoexcitations with an XFEL probe. They open new avenues for manipulating and researching the behaviour of photoexcited states in charge and spin order systems near the critical point.

Initial chest radiograph scores inform COVID-19 status, intensive care unit admission and need for mechanical ventilation.

AIM: To evaluate whether portable chest radiography (CXR) scores are associated with coronavirus disease 2019 (COVID-19) status and various clinical outcomes. MATERIALS AND METHODS: This retrospective study included 500 initial CXR from COVID-19-suspected patients. Each CXR was scored based on geographic extent and degree of opacity as indicators of disease severity. COVID-19 status and clinical outcomes including intensive care unit (ICU) admission, mechanical ventilation, mortality, length of hospitalisation, and duration on ventilator were collected. Multivariable logistic regression analysis was performed to evaluate the relationship between CXR scores and COVID-19 status, CXR scores and clinical outcomes, adjusted for code status, age, gender and co-morbidities. RESULTS: The interclass correlation coefficients amongst raters were 0.94 and 0.90 for the extent score and opacity score, respectively. CXR scores were significantly (p < 0.01) associated with COVID-19 positivity (odd ratio [OR] = 1.49; 95% confidence interval [CI]: 1.27 - 1.75 for extent score and OR = 1.75; 95% CI: 1.42 - 2.15 for opacity score), ICU admission (OR = 1.19; 95% CI: 1.09 - 1.31 for extent score and OR = 1.26; 95% CI: 1.10 - 1.44 for opacity score), and invasive mechanical ventilation (OR = 1.22; 95% CI: 1.11 - 1.35 for geographic score and OR = 1.21; 95% CI: 1.05 - 1.38 for opacity score). CXR scores were not significantly different between survivors and non-survivors after adjusting for code status (p>0.05). CXR scores were not associated with length of hospitalisation or duration on ventilation (p>0.05). CONCLUSIONS: Initial CXR scores have prognostic value and are associated with COVID-19 positivity, ICU admission, and mechanical ventilation.

How has COVID-19 affected the treatment of osteoporosis? An IOF-NOF-ESCEO global survey.

The effects of COVID-19 have the potential to impact on the management of chronic diseases including osteoporosis. A global survey has demonstrated that these impacts include an increase in telemedicine consultations, delays in DXA scanning, interruptions in the supply of medications and reductions in parenteral medication delivery. INTRODUCTION: The COVID-19 pandemic has had profound effects on the health of the global population both directly, via the sequelae of the infection, and indirectly, including the relative neglect of chronic disease management. Together the International Osteoporosis Foundation and National Osteoporosis Foundation sought to ascertain the impact on osteoporosis management. METHODS: Questionnaires were electronically circulated to a sample of members of both learned bodies and included information regarding the location and specialty of respondents, current extent of face to face consultations, alterations in osteoporosis risk assessment, telemedicine experience, alterations to medication ascertainment and delivery and electronic health record (EHR) utilisation. Responses were collected, quantitative data analysed, and qualitative data assessed for recurring themes. RESULTS: Responses were received from 209 healthcare workers from 53 countries, including 28% from Europe, 24% from North America, 19% from the Asia Pacific region, 17% from the Middle East and 12% from Latin America. Most respondents were physicians (85%) with physician assistants, physical therapists and nurses/nurse practitioners represented in the sample. The main three specialties represented included rheumatology (40%), endocrinology (22%) and orthopaedics (15%). In terms of the type of patient contact, 33% of respondents conducted telephone consultations and 21% video consultations. Bone mineral density assessment by dual-energy X-ray absorptiometry (DXA) usage was affected with only 29% able to obtain a scan as recommended. The majority of clinicians (60%) had systems in place to identify patients receiving parenteral medication, and 43% of clinicians reported difficulty in arranging appropriate osteoporosis medications during the COVID-19 crisis. CONCLUSIONS: To conclude through surveying a global sample of osteoporosis healthcare professionals, we have observed an increase in telemedicine consultations, delays in DXA scanning, interrupted supply of medications and reductions in parenteral medication delivery.

A patient-level key performance indicator set to measure the effectiveness of fracture liaison services and guide quality improvement: a position paper of the IOF Capture the Fracture Working Group, National Osteoporosis Foundation and Fragility Fracture Network.

The International Osteoporosis Foundation (IOF) Capture the Fracture® Campaign with the Fragility Fracture Network (FFN) and National Osteoporosis Foundation (NOF) has developed eleven patient-level key performance indicators (KPIs) for fracture liaison services (FLSs) to guide quality improvement. INTRODUCTION: Fracture Liaison Services (FLSs) are recommended worldwide to reduce fracture risk after a sentinel fracture. Given not every FLS is automatically effective, the IOF Capture the Fracture working group has developed and implemented the Best Practice Framework to assess the organisational components of an FLS. We have now developed a complimentary KPI set that extends this assessment of performance to the patient level. METHODS: The Capture the Fracture working group in collaboration with the Fragility Fracture Network Secondary Fragility Fracture Special Interest Group and National Osteoporosis Foundation adapted existing metrics from the UK-based Fracture Liaison Service Database Audit to develop a patient-level KPI set for FLSs. RESULTS: Eleven KPIs were selected. The proportion of patients: with non-spinal fractures; with spine fractures (detected clinically and radiologically); assessed for fracture risk within 12 weeks of sentinel fracture; having DXA assessment within 12 weeks of sentinel fracture; having falls risk assessment; recommended anti-osteoporosis medication; commenced of strength and balance exercise intervention within 16 weeks of sentinel fracture; monitored within 16 weeks of sentinel fracture; started anti-osteoporosis medication within 16 weeks of sentinel fracture; prescribed anti-osteoporosis medication 52 weeks after sentinel fracture. The final KPI measures data completeness for each of the other KPIs. For these indicators, levels of achievement were set at the < 50%, 50-80% and > 80% levels except for treatment recommendation where a level of 50% was used. CONCLUSION: This KPI set compliments the existing Best Practice Framework to support FLSs to examine their own performance using patient-level data. By using this KPI set for local quality improvement cycles, FLSs will be able to efficiently realise the full potential of secondary fracture prevention and improved clinical outcomes for their local populations.

Implementing routine communication about costs of cancer treatment: perspectives of providers, patients, and caregivers.

OBJECTIVES: Rising costs in oncology care often impact patients and families directly, making communication about costs and financial impacts of treatment crucial. Cost expenditures could offer opportunities for estimation and prediction, affording personalized conversations about financial impact. We sought to explore providers', patients', and caregivers' preferences towards implementing communication about cost, including when, how, and by whom such information might be provided. METHODS: We conducted semi-structured phone interviews with a diverse population including 12 oncology providers, 12 patients, and 8 patient caregivers (N = 32). The constant comparative method was used to identify mutually agreed upon themes. RESULTS: Participant groups differed in their concerns surrounding cost communication, namely whether they want to receive this information and how such information might impact provider and patient treatment decisions. All participants agreed that oncology providers should not be leading cost conversations. Patients and caregivers identified social workers or financial advisors as most equipped to communicate about cost. Participants emphasized timely cost conversations, ideally around the time of diagnosis. Participants favored various metrics of financial impact beyond overall costs of care including disability, days lost from work, and out-of-pocket expenses. CONCLUSION: Cost transparency should be incorporated into usual care; however, there are several challenges to making cost conversations a part of everyday practice. Patients and family members need resources related to cost to aid in decision-making and those delivering cost information should have competency in oncology, financial advisement, and patient-centered care.

Effects of Small Temperature Differences Detected in Callosal Circuits of the Anterior Cingulate Cortex.

We measured the sensitivity of cortical circuit activity to small differences in local cortical environments by studying how temperature affects the trajectory of epileptiform events (EEs). EEs evoked via blockade of GABA-A receptors were recorded extracellularly from mouse coronal brain slices containing both hemispheres of anterior cingulate cortex synaptically connected by corpus callosum axons. Preferentially illuminating one hemisphere with the microscope condenser produced temperature differences of 0.1 °C between the hemispheres. The relatively warmer hemisphere typically initiated the EEs that then propagated to the contralateral side, demonstrating temperature directed propagation. Severing the callosum following one hour of EEs showed that the warmer hemisphere possessed a higher rate of EE generation. Further experiments implied that intact callosal circuits were required for the increased EE generation in the warmer hemisphere. We propose a hypothesis whereby callosal circuits can amplify differences in respective hemispheric activity, promoting this directionality in seizure propagation.

Incidence and temporal trends of co-occurring personality disorder diagnoses in immune-mediated inflammatory diseases.

AIMS: Although immune-mediated inflammatory diseases (IMID) are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders (PDs) in these populations. We aimed to estimate and compare the incidence of any PD in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of PD. METHODS: We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. PDs were identified using hospitalisation or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of PDs between the IMID and matched cohorts. RESULTS: We identified 19 572 incident cases of IMID (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the IMID cohort had an increased incidence of PDs (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of PDs was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of PDs, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after IMID diagnosis, the incidence of PDs was also elevated before IMID diagnosis among all IMID groups relative to matched controls. CONCLUSIONS: IMID are associated with an increased incidence of PDs both before and after an IMID diagnosis. These results support the relevance of shared risk factors in the co-occurrence of PDs and IMID conditions.

Can Linked Electronic Medical Record and Administrative Data Help Us Identify Those Living with Frailty?

INTRODUCTION: Frailty is a complex condition that affects many aspects of patients' wellbeing and health outcomes. OBJECTIVES: We used available Electronic Medical Record (EMR) and administrative data to determine definitions of frailty. We also examined whether there were differences in demographics or health conditions among those identified as frail in either the EMR or administrative data. METHODS: EMR and administrative data were linked in British Columbia (BC) and Manitoba (MB) to identify those aged 65 years and older who were frail. The EMR data were obtained from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) and the administrative data (e.g. billing, hospitalizations) was obtained from Population Data BC and the Manitoba Population Research Data Repository. Sociodemographic characteristics, risk factors, prescribed medications, use and costs of healthcare are described for those identified as frail. RESULTS: Sociodemographic and utilization differences were found among those identified as frail from the EMR compared to those in the administrative data. Among those who were >65 years, who had a record in both EMR and administrative data, 5%-8% (n=191 of 3,553, BC; n=2,396 of 29,382, MB) were identified as frail. There was a higher likelihood of being frail with increasing age and being a woman. In BC and MB, those identified as frail in both data sources have approximately twice the number of contacts with primary care (n=20 vs. n=10) and more days in hospital (n=7.2 vs. n=1.9 in BC; n=9.8 vs. n=2.8 in MB) compared to those who are not frail; 27% (BC) and 14% (MB) of those identified as frail in 2014 died in 2015. CONCLUSIONS: Identifying frailty using EMR data is particularly challenging because many functional deficits are not routinely recorded in structured data fields. Our results suggest frailty can be captured along a continuum using both EMR and administrative data.

Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates.

Transitioning postmenopausal women with osteoporosis from a bisphosphonate to denosumab appears to be safe and more effective at improving BMD than continuing treatment with a bisphosphonate. INTRODUCTION: We conducted a patient-level pooled analysis of four studies to estimate the efficacy and safety of transitioning to denosumab vs. continuing bisphosphonate treatment in postmenopausal women who previously received oral bisphosphonates. METHODS: Patients received 60 mg denosumab once every 6 months or a bisphosphonate (oral alendronate, risedronate, ibandronate, or intravenous zoledronic acid). Endpoints were change from baseline in lumbar spine, total hip, femoral neck, and 1/3 radius BMD at month 12, change from baseline in serum CTX-1 and P1NP, and incidence of adverse events. RESULTS: A total of 2850 randomized patients (1424 bisphosphonate:1426 denosumab) were included in the analysis. Percentage change in BMD was significantly greater (p < 0.001) for denosumab vs. bisphosphonate at each skeletal site; differences in BMD changes ranged from 0.6 to 2.0%. Percentage decrease in serum CTX-1 and P1NP was significantly greater (p < 0.0001) for denosumab vs. bisphosphonate at months 1, 6, and 12; in the denosumab group only, percentage change in serum CTX-1 at month 1 was significantly correlated with percentage change in lumbar spine and total hip BMD at month 12. The incidences of adverse events were similar between treatment groups. Three patients (one bisphosphonate and two denosumab) had atypical femoral fractures, all from the denosumab vs. zoledronic acid study. CONCLUSION: Postmenopausal women can safely transition from a bisphosphonate to denosumab, which is more effective at improving BMD than continuing with a bisphosphonate. CLINICAL TRIALS REGISTRATION: NCT00377819, NCT00919711, NCT00936897, NCT01732770.