How context can impact clinical trials : a multi-country qualitative case study comparison of diagnostic biomarker test interventions

Background Context matters for the successful implementation of medical interventions, but its role remains surprisingly understudied. Against the backdrop of antimicrobial resistance, a global health priority, we investigated the introduction of a rapid diagnostic biomarker test (C-reactive protein, or CRP) to guide antibiotic prescriptions in outpatient settings and asked, “Which factors account for cross-country variations in the effectiveness of CRP biomarker test interventions?” Methods We conducted a cross-case comparison of CRP point-of-care test trials across Yangon (Myanmar), Chiang Rai (Thailand), and Hanoi (Vietnam). Cross-sectional qualitative data were originally collected as part of each clinical trial to broaden their evidence base and help explain their respective results. We synthesised these data and developed a large qualitative data set comprising 130 interview and focus group participants (healthcare workers and patients) and nearly one million words worth of transcripts and interview notes. Inductive thematic analysis was used to identify contextual factors and compare them across the three case studies. As clinical trial outcomes, we considered patients’ and healthcare workers’ adherence to the biomarker test results, and patient exclusion to gauge the potential “impact” of CRP point-of-care testing on the population level. Results We identified three principal domains of contextual influences on intervention effectiveness. First, perceived risks from infectious diseases influenced the adherence of the clinical users (nurses, doctors). Second, the health system context related to all three intervention outcomes (via the health policy and antibiotic policy environment, and via health system structures and the ensuing utilisation patterns). Third, the demand-side context influenced the patient adherence to CRP point-of-care tests and exclusion from the intervention through variations in local healthcare-seeking behaviours, popular conceptions of illness and medicine, and the resulting utilisation of the health system. Conclusions Our study underscored the importance of contextual variation for the interpretation of clinical trial findings. Further research should investigate the range and magnitude of contextual effects on trial outcomes through meta-analyses of large sets of clinical trials. For this to be possible, clinical trials should collect qualitative and quantitative contextual information for instance on their disease, health system, and demand-side environment. Trial registration: ClinicalTrials.gov Identifiers NCT02758821 and NCT01918579

Further Closing the Resolution Gap: Integrating Cryo-Soft X-Ray and Light Microscopies

Abstract Water megamasers from circumnuclear disks in galaxy centers provide the most accurate measurements of supermassive black hole masses and uniquely probe the subparsec accretion processes. At the same time, these systems offer independent crucial constraints of the Hubble constant in the nearby universe, and thus, the arguably best single constraint on the nature of dark energy. The chances of finding these golden standards are, however, abysmally low, at ?3% overall for any level of water maser emission detected at 22 GHz and ?1% for those exhibiting disk-like configuration. We provide here a thorough summary of the current state of detection of water megamaser disks along with a novel investigation of the likelihood of increasing their detection rates based on a multivariate parameter analysis of the optical and mid-infrared (mid-IR) photometric properties of the largest database of galaxies surveyed for 22 GHz emission. We find that galaxies with water megamaser emission tend to be associated with strong emission in all Wide-field Infrared Survey Explorer mid-IR wavelengths, with the strongest enhancement in the W4 band, at 22 μm, as well as with previously proposed and newly found indicators of active galactic nucleus strength in the mid-IR, such as red W1???W2 and W1???W4 colors, and the integrated mid-IR luminosity of the host galaxy. These trends offer a potential boost of the megamaser detection rates to 6%–15%, or a factor of 2–8 relative to the current rates, depending on the chosen sample selection criteria, while fostering real chances for discovering ?20 new megamaser disks

NuSTAR observations of water megamaser AGN

Aims. We study the connection between the masing disk and obscuring torus in Seyfert 2 galaxies. Methods. We present a uniform X-ray spectral analysis of the high energy properties of 14 nearby megamaser active galactic nuclei observed by NuSTAR. We use a simple analytical model to localize the maser disk and understand its connection with the torus by combining NuSTAR spectral parameters with the available physical quantities from VLBI mapping. Results. Most of the sources that we analyzed are heavily obscured, showing a column density in excess of ~10^(23) cm^(-2); in particular, 79% are Compton-thick (N_H > 1.5 × 10^(24) cm^(-2)). When using column densities measured by NuSTAR with the assumption that the torus is the extension of the maser disk, and further assuming a reasonable density profile, we can predict the torus dimensions. They are found to be consistent with mid-IR interferometry parsec-scale observations of Circinus and NGC 1068. In this picture, the maser disk is intimately connected to the inner part of the torus. It is probably made of a large number of molecular clouds that connect the torus and the outer part of the accretion disk, giving rise to a thin disk rotating in most cases in Keplerian or sub-Keplerian motion. This toy model explains the established close connection between water megamaser emission and nuclear obscuration as a geometric effect

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): Exome sequencing of trios, monozygotic twins and tumours

BACKGROUND: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients. METHODS: We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons. RESULTS: The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations. CONCLUSIONS: Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0314-x) contains supplementary material, which is available to authorized users

Potential of Magnetic Hyperthermia to Stimulate Localized Immune Activation

Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n = 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response

Operations of and Future Plans for the Pierre Auger Observatory

Technical reports on operations and features of the Pierre Auger Observatory, including ongoing and planned enhancements and the status of the future northern hemisphere portion of the Observatory. Contributions to the 31st International Cosmic Ray Conference, Lodz, Poland, July 2009.Comment: Contributions to the 31st ICRC, Lodz, Poland, July 200