All nonadherence is equal but is some more equal than others? Tuberculosis in the digital era

Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address nonadherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy – as adopted by the international adherence community – to dose-by-dose medication-taking data, which divides missed doses into 1) late/noninitiation (starting treatment later than expected/not starting), 2) discontinuation (ending treatment early), and 3) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of nonadherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the “forgiveness” of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress

Hot flow anomalies at Venus

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95474/1/jgra21752.pd

Short Large-Amplitude Magnetic Structures (SLAMS) at Venus

We present the first observation of magnetic fluctuations consistent with Short Large-Amplitude Magnetic Structures (SLAMS) in the foreshock of the planet Venus. Three monolithic magnetic field spikes were observed by the Venus Express on the 11th of April 2009. The structures were approx.1.5->11s in duration, had magnetic compression ratios between approx.3->6, and exhibited elliptical polarization. These characteristics are consistent with the SLAMS observed at Earth, Jupiter, and Comet Giacobini-Zinner, and thus we hypothesize that it is possible SLAMS may be found at any celestial body with a foreshock

Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production

Intestinal microbiota are critical for health with changes associated with diverse human diseases. Research suggests that altered intestinal microbiota can profoundly affect brain function. However, whether altering brain function directly affects the microbiota is unknown. Since it is currently unclear how brain injury induces clinical complications such as infections or paralytic ileus, key contributors to prolonged hospitalization and death post-stroke, we tested in mice the hypothesis that brain damage induced changes in the intestinal microbiota. Experimental stroke altered the composition of caecal microbiota, with specific changes in Peptococcaceae and Prevotellaceae correlating with the extent of injury. These effects are mediated by noradrenaline release from the autonomic nervous system with altered caecal mucoprotein production and goblet cell numbers. Traumatic brain injury also caused changes in the gut microbiota, confirming brain injury effects gut microbiota. Changes in intestinal microbiota after brain injury may affect recovery and treatment of patients should appreciate such changes

Evaluation of Brain Nuclear Medicine Imaging Tracers in a Murine Model of Sepsis-Associated Encephalopathy

PURPOSE: The purpose of this study was to evaluate a set of widely used nuclear medicine imaging agents as possible methods to study the early effects of systemic inflammation on the living brain in a mouse model of sepsis-associated encephalopathy (SAE). The lipopolysaccharide (LPS)-induced murine systemic inflammation model was selected as a model of SAE. PROCEDURES: C57BL/6 mice were used. A multimodal imaging protocol was carried out on each animal 4 h following the intravenous administration of LPS using the following tracers: [(99m)Tc][2,2-dimethyl-3-[(3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(3E)-3-hyd roxyiminobutan-2-yl]azanide ([(99m)Tc]HMPAO) and ethyl-7-[(125)I]iodo-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbox ylate ([(125)I]iomazenil) to measure brain perfusion and neuronal damage, respectively; 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) to measure cerebral glucose uptake. We assessed microglia activity on another group of mice using 2-[6-chloro-2-(4-[(125)I]iodophenyl)-imidazo[1,2-a]pyridin-3-yl]-N-ethyl-N-methyl -acetamide ([(125)I]CLINME). Radiotracer uptakes were measured in different brain regions and correlated. Microglia activity was also assessed using immunohistochemistry. Brain glutathione levels were measured to investigate oxidative stress. RESULTS: Significantly reduced perfusion values and significantly enhanced [(18)F]FDG and [(125)I]CLINME uptake was measured in the LPS-treated group. Following perfusion compensation, enhanced [(125)I]iomazenil uptake was measured in the LPS-treated group's hippocampus and cerebellum. In this group, both [(18)F]FDG and [(125)I]iomazenil uptake showed highly negative correlation to perfusion measured with ([(99m)Tc]HMPAO uptake in all brain regions. No significant differences were detected in brain glutathione levels between the groups. The CD45 and P2Y12 double-labeling immunohistochemistry showed widespread microglia activation in the LPS-treated group. CONCLUSIONS: Our results suggest that [(125)I]CLINME and [(99m)Tc]HMPAO SPECT can be used to detect microglia activation and brain hypoperfusion, respectively, in the early phase (4 h post injection) of systemic inflammation. We suspect that the enhancement of [(18)F]FDG and [(125)I]iomazenil uptake in the LPS-treated group does not necessarily reflect neural hypermetabolism and the lack of neuronal damage. They are most likely caused by processes emerging during neuroinflammation, e.g., microglia activation and/or immune cell infiltration

Perspectives for systems biology in the management of tuberculosis

Standardised management of tuberculosis may soon be replaced by individualised, precision medicine-guided therapies informed with knowledge provided by the field of systems biology. Systems biology is a rapidly expanding field of computational and mathematical analysis and modelling of complex biological systems that can provide insights into mechanisms underlying tuberculosis, identify novel biomarkers, and help to optimise prevention, diagnosis and treatment of disease. These advances are critically important in the context of the evolving epidemic of drug-resistant tuberculosis. Here, we review the available evidence on the role of systems biology approaches - human and mycobacterial genomics and transcriptomics, proteomics, lipidomics/metabolomics, immunophenotyping, systems pharmacology and gut microbiomes - in the management of tuberculosis including prediction of risk for disease progression, severity of mycobacterial virulence and drug resistance, adverse events, comorbidities, response to therapy and treatment outcomes. Application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach demonstrated that at present most of the studies provide "very low" certainty of evidence for answering clinically relevant questions. Further studies in large prospective cohorts of patients, including randomised clinical trials, are necessary to assess the applicability of the findings in tuberculosis prevention and more efficient clinical management of patients