Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers

Atypical depression is more common than melancholic in fibromyalgia: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>It has been postulated that atypical and melancholic depression subtypes exist in depressed fibromyalgia (FM) patients, yet no study has empirically tested this hypothesis. The purpose of this study is to determine whether major depressive disorder (MDD) with atypical features and MDD with melancholic features occurs in a FM sample and to describe their demographic, clinical and diagnostic characteristics.</p> <p>Methods</p> <p>An observational cohort study using a descriptive cross-sectional design recruited a convenience sample of 76 outpatients with FM from an academic Rheumatology clinic and a community mental health practice. Diagnoses of FM were confirmed using the 1990 ACR classification guidelines. Diagnoses of MDD and diagnostic subtypes were determined using the DSM-IV-TR criteria. Clinical characteristics were measured using the Fibromyalgia Impact Questionnaire, Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and other standardized instruments. Odds ratios were computed on subtype-specific diagnostic criteria. Correlations assessed associations between subtype diagnoses and diagnostic criteria.</p> <p>Results</p> <p>Of the 76 subjects with FM, 11.8% (n = 9) were euthymic, 52.6% (n = 40) met diagnostic criteria for MDD with atypical features and 35.6% (n = 27) for MDD with melancholic features. Groups did not differ on demographic characteristics except for gender (p = 0.01). The non-depressed and atypical groups trended toward having a longer duration of FM symptoms (18.05 yrs. ± 12.83; 20.36 yrs. ± 15.07) compared to the melancholic group (14.11 yrs. ± 8.82; p = 0.09). The two depressed groups experienced greater severity on all clinical features compared to the non-depressed group. The atypical group did not differ clinically from the melancholic group except the latter experienced greater depression severity (p = 0.001). The atypical group demonstrated the highest prevalence and correlations with atypical-specific diagnostic criteria: (e.g., weight gain/ increased appetite: OR = 3.5, p = 0.02), as did the melancholic group for melancholic-specific criteria: (e.g., anhedonia: OR = 20, p < 0.001).</p> <p>Conclusion</p> <p>Depressed fibromyalgia patients commonly experience both atypical and melancholic depressive features; however, in this study, atypical depression was 1.5 times more common than melancholic depression. This finding may have significant research and clinical implications.</p

SN 2015bn: A DETAILED MULTI-WAVELENGTH VIEW of A NEARBY SUPERLUMINOUS SUPERNOVA

We present observations of SN 2015bn (=PS15ae = CSS141223-113342+004332 = MLS150211-113342+004333), a Type I superluminous supernova (SLSN) at redshift z = 0.1136. As well as being one of the closest SLSNe I yet discovered, it is intrinsically brighter (${M}_{U}\approx -23.1$) and in a fainter galaxy (${M}_{B}\approx -16.0$) than other SLSNe at $z\sim 0.1$. We used this opportunity to collect the most extensive data set for any SLSN I to date, including densely sampled spectroscopy and photometry, from the UV to the NIR, spanning −50 to +250 days from optical maximum. SN 2015bn fades slowly, but exhibits surprising undulations in the light curve on a timescale of 30–50 days, especially in the UV. The spectrum shows extraordinarily slow evolution except for a rapid transformation between +7 and +20–30 days. No narrow emission lines from slow-moving material are observed at any phase. We derive physical properties including the bolometric luminosity, and find slow velocity evolution and non-monotonic temperature and radial evolution. A deep radio limit rules out a healthy off-axis gamma-ray burst, and places constraints on the pre-explosion mass loss. The data can be consistently explained by a $\gtrsim 10$ M ${}_{\odot }$ stripped progenitor exploding with $\sim {10}^{51}$ erg kinetic energy, forming a magnetar with a spin-down timescale of ~20 days (thus avoiding a gamma-ray burst) that reheats the ejecta and drives ionization fronts. The most likely alternative scenario—interaction with ~20 M ${}_{\odot }$ of dense, inhomogeneous circumstellar material—can be tested with continuing radio follow-up.S.J.S. acknowledges funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no [291222] and STFC grants ST/I001123/1 and ST/L000709/1. This work is based (in part) on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere, Chile as part of PESSTO, (the Public ESO Spectroscopic Survey for Transient Objects Survey) ESO program 188.D-3003, 191.D-0935. The Pan-STARRS1 Surveys (PS1) have been made possible through contributions of the Institute for Astronomy, the University of Hawaii, the Pan-STARRS Project Office, the Max-Planck Society and its participating institutes, the Max Planck Institute for Astronomy, Heidelberg and the Max Planck Institute for Extraterrestrial Physics, Garching, The Johns Hopkins University, Durham University, the University of Edinburgh, Queen's University Belfast, the Harvard-Smithsonian Center for Astrophysics, the Las Cumbres Observatory Global Telescope Network Incorporated, the National Central University of Taiwan, the Space Telescope Science Institute, the National Aeronautics and Space Administration under Grant No. NNX08AR22G issued through the Planetary Science Division of the NASA Science Mission Directorate, the National Science Foundation under Grant No. AST-1238877, the University of Maryland, and Eotvos Lorand University (ELTE). Operation of the Pan-STARRS1 telescope is supported by the National Aeronautics and Space Administration under Grant No. NNX12AR65G and Grant No. NNX14AM74G issued through the NEO Observation Program. Based on observations made with the Nordic Optical Telescope, operated by the Nordic Optical Telescope Scientific Association at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofisica de Canarias. A.G.-Y. is supported by the EU/FP7 via ERC grant No. 307260, the Quantum universe I-Core programme by the Israeli Committee for Planning and Budgeting and the ISF; by Minerva and ISF grants; by the Weizmann-UK "making connections" programme; and by the Kimmel and YeS awards. B.D.M. is supported by NSF grant AST-1410950 and the Alfred P. Sloan Foundation. Support for L.G. is provided by the Ministry of Economy, Development, and Tourism's Millennium Science Initiative through grant IC120009 awarded to The Millennium Institute of Astrophysics (MAS), and CONICYT through FONDECYT grant 3140566. This work was partly supported by the European Union FP7 programme through ERC grant number 320360. K.M. acknowledges support from the STFC through an Ernest Rutherford Fellowship. A.M. acknowledges funding from CNRS. Development of ASAS-SN has been supported by NSF grant AST-0908816 and CCAPP at the Ohio State University. ASAS-SN is supported by NSF grant AST-1515927, the Center for Cosmology and AstroParticle Physics (CCAPP) at OSU, the Mt. Cuba Astronomical Foundation, George Skestos, and the Robert Martin Ayers Sciences Fund. B.S. is supported by NASA through Hubble Fellowship grant HF-51348.001 awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS 5-26555. C.S.K. is supported by NSF grants AST-1515876 and AST-1515927. T.W.-S.H. is supported by the DOE Computational Science Graduate Fellowship, grant number DE-FG02-97ER25308. V.A.V. is supported by a NSF Graduate Research Fellowship. P.S.C. is grateful for support provided by the NSF through the Graduate Research Fellowship Program, grant DGE1144152. P.B. is supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE1144152. D.A.H., C.M., and G.H. are supported by NSF grant 1313484.This is the author accepted manuscript. The final version is available from the Institute of Physics via http://dx.doi.org/10.3847/0004-637X/826/1/3

LC/MS-Based Quantitative Proteomic Analysis of Paraffin-Embedded Archival Melanomas Reveals Potential Proteomic Biomarkers Associated with Metastasis

BACKGROUND: Melanoma metastasis status is highly associated with the overall survival of patients; yet, little is known about proteomic changes during melanoma tumor progression. To better understand the changes in protein expression involved in melanoma progression and metastasis, and to identify potential biomarkers, we conducted a global quantitative proteomic analysis on archival metastatic and primary melanomas. METHODOLOGY AND FINDINGS: A total of 16 metastatic and 8 primary cutaneous melanomas were assessed. Proteins were extracted from laser captured microdissected formalin fixed paraffin-embedded archival tissues by liquefying tissue cells. These preparations were analyzed by a LC/MS-based label-free protein quantification method. More than 1500 proteins were identified in the tissue lysates with a peptide ID confidence level of >75%. This approach identified 120 significant changes in protein levels. These proteins were identified from multiple peptides with high confidence identification and were expressed at significantly different levels in metastases as compared with primary melanomas (q-Value<0.05). CONCLUSIONS AND SIGNIFICANCE: The differentially expressed proteins were classified by biological process or mapped into biological system networks, and several proteins were implicated by these analyses as cancer- or metastasis-related. These proteins represent potential biomarkers for tumor progression. The study successfully identified proteins that are differentially expressed in formalin fixed paraffin-embedded specimens of metastatic and primary melanoma

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity

Mammalian sex determination—insights from humans and mice

Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models

SN 2017ivv: two years of evolution of a transitional Type II supernova

We present the photometric and spectroscopic evolution of the Type II supernova (SN II) SN 2017ivv (also known as ASASSN-17qp). Located in an extremely faint galaxy (M$_r=-10.3$ mag), SN 2017ivv shows an unprecedented evolution during the two years of observations. At early times, the light curve shows a fast rise ($\sim6-8$ days) to a peak of ${\rm M}^{\rm max}_{g}= -17.84$ mag, followed by a very rapid decline of $7.94\pm0.48$ mag per 100 days in the $V-$band. The extensive photometric coverage at late phases shows that the radioactive tail has two slopes, one steeper than that expected from the decay of $^{56}$Co (between 100 and 350 days), and another slower (after 450 days), probably produced by an additional energy source. From the bolometric light curve, we estimated that the amount of ejected $^{56}$Ni is $\sim0.059\pm0.003$ M$\odot$. The nebular spectra of SN 2017ivv show a remarkable transformation that allows the evolution to be split into three phases: (1) H$\alpha$ strong phase ($500$ days). We find that the nebular analysis favours a binary progenitor and an asymmetric explosion. Finally, comparing the nebular spectra of SN 2017ivv to models suggests a progenitor with a zero-age main-sequence mass of 15 -- 17 \Msun

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams