366 research outputs found

    Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study

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    Background/aims: In multi-site clinical trials, where trial data and conduct are scrutinised centrally with pre-specified triggers for visits to sites, targeted monitoring may be an efficient way to prioritise on-site monitoring. This approach is widely used in academic trials, but has never been formally evaluated. // Methods: TEMPER assessed the ability of targeted monitoring, as used in three ongoing phase III randomised multi-site oncology trials, to distinguish sites at which higher and lower rates of protocol and/or Good Clinical Practice violations would be found during site visits. Using a prospective, matched-pair design, sites that had been prioritised for visits after having activated ‘triggers’ were matched with a control (‘untriggered’) site, which would not usually have been visited at that time. The paired sites were visited within 4 weeks of each other, and visit findings are recorded and categorised according to the seriousness of the deviation. The primary outcome measure was the proportion of sites with ≥1 ‘Major’ or ‘Critical’ finding not previously identified centrally. The study was powered to detect an absolute difference of ≥30% between triggered and untriggered visits. A sensitivity analysis, recommended by the study’s blinded endpoint review committee, excluded findings related to re-consent. Additional analyses assessed the prognostic value of individual triggers and data from pre-visit questionnaires completed by site and trials unit staff. // Results: In total, 42 matched pairs of visits took place between 2013 and 2016. In the primary analysis, 88.1% of triggered visits had ≥1 new Major/Critical finding, compared to 81.0% of untriggered visits, an absolute difference of 7.1% (95% confidence interval −8.3%, +22.5%; p = 0.365). When re-consent findings were excluded, these figures reduced to 85.7% versus 59.5%, (difference = 26.2%, 95% confidence interval 8.0%, 44.4%; p = 0.007). Individual triggers had modest prognostic value but knowledge of the trial-related activities carried out by site staff may be useful. // Conclusion: Triggered monitoring approaches, as used in these trials, were not sufficiently discriminatory. The rate of Major and Critical findings was higher than anticipated, but the majority related to consent and re-consent with no indication of systemic problems that would impact trial-wide safety issues or integrity of the results in any of the three trials. Sensitivity analyses suggest triggered monitoring may be of potential use, but needs improvement and investigation of further central monitoring triggers is warranted. TEMPER highlights the need to question and evaluate methods in trial conduct, and should inform further developments in this area

    BK Channels Regulate Spontaneous Action Potential Rhythmicity in the Suprachiasmatic Nucleus

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    Background: Circadian (,24 hr) rhythms are generated by the central pacemaker localized to the suprachiasmatic nucleus (SCN) of the hypothalamus. Although the basis for intrinsic rhythmicity is generally understood to rely on transcription factors encoded by ‘‘clock genes’’, less is known about the daily regulation of SCN neuronal activity patterns that communicate a circadian time signal to downstream behaviors and physiological systems. Action potentials in the SCN are necessary for the circadian timing of behavior, and individual SCN neurons modulate their spontaneous firing rate (SFR) over the daily cycle, suggesting that the circadian patterning of neuronal activity is necessary for normal behavioral rhythm expression. The BK K + channel plays an important role in suppressing spontaneous firing at night in SCN neurons. Deletion of the Kcnma1 gene, encoding the BK channel, causes degradation of circadian behavioral and physiological rhythms. Methodology/Principal Findings: To test the hypothesis that loss of robust behavioral rhythmicity in Kcnma1 2/2 mice is due to the disruption of SFR rhythms in the SCN, we used multi-electrode arrays to record extracellular action potentials from acute wild-type (WT) and Kcnma1 2/2 slices. Patterns of activity in the SCN were tracked simultaneously for up to 3 days, and the phase, period, and synchronization of SFR rhythms were examined. Loss of BK channels increased arrhythmicity but also altered the amplitude and period of rhythmic activity. Unexpectedly, Kcnma1 2/2 SCNs showed increased variability in the timing of the daily SFR peak

    The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

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    PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

    Stabilization of dense Antarctic water supply to the Atlantic Ocean overturning circulation

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    The lower limb of the Atlantic overturning circulation is resupplied by the sinking of dense Antarctic Bottom Water (AABW) that forms via intense air–sea–ice interactions next to Antarctica, especially in the Weddell Sea. In the last three decades, AABW has warmed, freshened and declined in volume across the Atlantic Ocean and elsewhere, suggesting an ongoing major reorganization of oceanic overturning. However, the future contributions of AABW to the Atlantic overturning circulation are unclear. Here, using observations of AABW in the Scotia Sea, the most direct pathway from the Weddell Sea to the Atlantic Ocean, we show a recent cessation in the decline of the AABW supply to the Atlantic overturning circulation. The strongest decline was observed in the volume of the densest layers in the AABW throughflow from the early 1990s to 2014; since then, it has stabilized and partially recovered. We link these changes to variability in the densest classes of abyssal waters upstream. Our findings indicate that the previously observed decline in the supply of dense water to the Atlantic Ocean abyss may be stabilizing or reversing and thus call for a reassessment of Antarctic influences on overturning circulation, sea level, planetary-scale heat distribution and global climate

    Transcriptional Reprogramming of CD11b+Esamhi Dendritic Cell Identity and Function by Loss of Runx3

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    Classical dendritic cells (cDC) are specialized antigen-presenting cells mediating immunity and tolerance. cDC cell-lineage decisions are largely controlled by transcriptional factor regulatory cascades. Using an in vivo cell-specific targeting of Runx3 at various stages of DC lineage development we show that Runx3 is required for cell-identity, homeostasis and function of splenic Esamhi DC. Ablation of Runx3 in DC progenitors led to a substantial decrease in splenic CD4+/CD11b+ DC. Combined chromatin immunoprecipitation sequencing and gene expression analysis of purified DC-subsets revealed that Runx3 is a key gene expression regulator that facilitates specification and homeostasis of CD11b+Esamhi DC. Mechanistically, loss of Runx3 alters Esamhi DC gene expression to a signature characteristic of WT Esamlow DC. This transcriptional reprogramming caused a cellular change that diminished phagocytosis and hampered Runx3-/- Esamhi DC capacity to prime CD4+ T cells, attesting to the significant role of Runx3 in specifying Esamhi DC identity and function

    Attitudes and Practices Among Internists Concerning Genetic Testing

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    Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8 %), followed by Breast/Ovarian Cancer (15.0 %). In the past 6 months, 65 % had counseled patients on genetic issues, 44 % had ordered genetic tests, 38.5 % had referred patients to a genetic counselor or geneticist, and 27.5 % had received ads from commercial labs for genetic testing. Only 4.5 % had tried to hide or disguise genetic information, and <2 % have had patients report genetic discrimination. Only 53.4 % knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7 %) and guidelines for genetic testing (87.1 %). Most felt needs for more training on when to order tests (79 %), and how to counsel patients (82 %), interpret results (77.3 %), and maintain privacy (80.6 %). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p  < .001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p  < .002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p  < .019), counseled patients about genetics, larger practices (p  < .032), fewer African‐American patients (p  < .027), and patients who had reported genetic discrimination (p  < .044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests. These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education

    Evidence of an active volcanic heat source beneath the Pine Island Glacier

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    Tectonic landforms reveal that the West Antarctic Ice Sheet (WAIS) lies atop a major volcanic rift system. However, identifying subglacial volcanism is challenging. Here we show geochemical evidence of a volcanic heat source upstream of the fast-melting Pine Island Ice Shelf, documented by seawater helium isotope ratios at the front of the Ice Shelf cavity. The localization of mantle helium to glacial meltwater reveals that volcanic heat induces melt beneath the grounded glacier and feeds the subglacial hydrological network crossing the grounding line. The observed transport of mantle helium out of the Ice Shelf cavity indicates that volcanic heat is supplied to the grounded glacier at a rate of ~ 2500 ± 1700 MW, which is ca. half as large as the active Grimsvötn volcano on Iceland. Our finding of a substantial volcanic heat source beneath a major WAIS glacier highlights the need to understand subglacial volcanism, its hydrologic interaction with the marine margins, and its potential role in the future stability of the WAIS

    Sí Se Puede: Using Participatory Research to Promote Environmental Justice in a Latino Community in San Diego, California

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    Community-based participatory research (CBPR) increasingly is seen as a potent tool for studying and addressing urban environmental health problems by linking place-based work with efforts to help effect policy-level change. This paper explores a successful CBPR and organizing effort, the Toxic Free Neighborhoods Campaign, in Old Town National City (OTNC), CA, United States, and its contributions to both local policy outcomes and changes in the broader policy environment, laying the groundwork for a Specific Plan to address a host of interlocking community concerns. After briefly describing the broader research of which the OTNC case study was a part, we provide background on the Environmental Health Coalition (EHC) partnership and the setting in which it took place, including the problems posed for residents in this light industrial/residential neighborhood. EHC’s strong in-house research, and its training and active engagement of promotoras de salud (lay health promoters) as co-researchers and policy change advocates, are described. We explore in particular the translation of research findings as part of a policy advocacy campaign, interweaving challenges faced and success factors and multi-level outcomes to which these efforts contributed. The EHC partnership's experience then is compared with that of other policy-focused CBPR efforts in urban environmental health, emphasizing common success factors and challenges faced, as these may assist other partnerships wishing to pursue CBPR in urban communities

    Tracking down carbon inputs underground from an arid zone Australian calcrete.

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    Freshwater ecosystems play a key role in shaping the global carbon cycle and maintaining the ecological balance that sustains biodiversity worldwide. Surficial water bodies are often interconnected with groundwater, forming a physical continuum, and their interaction has been reported as a crucial driver for organic matter (OM) inputs in groundwater systems. However, despite the growing concerns related to increasing anthropogenic pressure and effects of global change to groundwater environments, our understanding of the dynamics regulating subterranean carbon flows is still sparse. We traced carbon composition and transformations in an arid zone calcrete aquifer using a novel multidisciplinary approach that combined isotopic analyses of dissolved organic carbon (DOC) and inorganic carbon (DIC) (δ13CDOC, δ13CDIC, 14CDOC and 14CDIC) with fluorescence spectroscopy (Chromophoric Dissolved OM (CDOM) characterisation) and metabarcoding analyses (taxonomic and functional genomics on bacterial 16S rRNA). To compare dynamics linked to potential aquifer recharge processes, water samples were collected from two boreholes under contrasting rainfall: low rainfall ((LR), dry season) and high rainfall ((HR), wet season). Our isotopic results indicate limited changes and dominance of modern terrestrial carbon in the upper part (northeast) of the bore field, but correlation between HR and increased old and 13C-enriched DOC in the lower area (southwest). CDOM results show a shift from terrestrially to microbially derived compounds after rainfall in the same lower field bore, which was also sampled for microbial genetics. Functional genomic results showed increased genes coding for degradative pathways-dominated by those related to aromatic compound metabolisms-during HR. Our results indicate that rainfall leads to different responses in different parts of the bore field, with an increase in old carbon sources and microbial processing in the lower part of the field. We hypothesise that this may be due to increasing salinity, either due to mobilisation of Cl- from the soil, or infiltration from the downstream salt lake during HR. This study is the first to use a multi-technique assessment using stable and radioactive isotopes together with functional genomics to probe the principal organic biogeochemical pathways regulating an arid zone calcrete system. Further investigations involving extensive sampling from diverse groundwater ecosystems will allow better understanding of the microbiological pathways sustaining the ecological functioning of subterranean biota
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