Background. The treatment of extensively drug-resistant tuberculosis (XDR TB) presents a major challenge. Second-line antimycobacterial drugs are less effective, more toxic, and more costly than ...first-line agents, and XDR TB strains are, by definition, resistant to the most potent second-line options: the injectable agents and fluoroquinolones. We conducted a meta-analysis to assess XDR TB treatment outcomes and to identify therapeutic approaches associated with favorable responses. Methods. We searched PubMed and EMBASE databases to identify studies conducted through May 2009 that report XDR TB treatment outcomes. Results. The search yielded 13 observational studies covering 560 patients, of whom 43.7% (95% confidence interval, 32.8%–54.5%) experienced favorable outcomes, defined as either cure or treatment completion, and 20.8% (95% confidence interval, 14.2%–27.3%) died. Random effects meta-analysis and meta-regression showed that studies in which a higher proportion of patients received a later-generation fluoroquinolone reported a higher proportion of favorable treatment outcomes (P = .012). Conclusions. This meta-analysis provides the first empirical evidence that the use of later-generation fluoroquinolones for the treatment of XDR TB significantly improves treatment outcomes, even though drug-susceptibility testing demonstrates resistance to a representative fluoroquinolone. These results suggest that the addition of latergeneration fluoroquinolones to XDR TB regimens may improve treatment outcomes and should be systematically evaluated in well-designed clinical studies.
•An expectation in aquatic toxicology is that fish move away from toxic chemicals.•Fish avoid various pesticides, metals, gases, hydrocarbons and effluents.•Fish may be attracted to the same types of ...chemicals or their mixtures.•Models to predict avoidance or prescribe testing are provided.•A challenge is to protect fish in field through the use of chemical stimuli.
The hydrosphere is a repository for all of our waste and mistakes, be they sewage, garbage, process-affected waters, runoff, and gases. For fish living in environments receiving undesirable inputs, moving away seems an obvious way to avoid harm. While this should occur, there are numerous examples where it will not. The inability to avoid harmful environments may lead to sensory impairments that in turn limit the ability to avoid other dangers or locate benefits. For avoidance to occur, the danger must first be perceived, which may not happen if the fish is ‘blinded’ in some capacity. Second, the danger must be recognized for what it is, which may also not happen if the fish is cognitively confused or impaired. Third, it is possible that the fish may not be able to leave the area, or worse, learns to prefer a toxic environment. Concerning generating regulations around avoidance, there are two possibilities: that an avoidance threshold be used to set guidelines for effluent release with the intention of driving fishes away; the second is to set a contaminant concentration that would not affect the avoidance or attraction responses to other cues. With the complexities of the modern world in which we release diverse pollutants, from light to municipal effluents full of 1000s of chemicals, to the diversity present in ecosystems, it is impossible to have avoidance data on every stimulus-species combination. Nevertheless, we may be able to use existing avoidance response data to predict the likelihood of avoidance of untested stimuli. Where we cannot, this review includes a framework that can be used to direct new research. This review is intended to collate existing avoidance response data, provide a framework for making decisions in the absence of data, and suggest studies that would facilitate the prediction of risk to fish health in environments receiving intentional and unintentional human-based chemical inputs.
Intentional integration of knowledge from both K-12 practice and teacher preparation theories supports emerging teacher educators' hybrid identity development. In this collaborative self-study, three ...teacher educators reflected upon the negotiation of tensions that arose in their efforts to promote culturally and linguistically responsive pedagogy in K-12 and teacher education settings. Individual journals, recorded critical friend discussions, and teaching artifacts were used as data to support teacher educators' critical reflections on their own practice and identity development. Data collection spanned teacher educators' experiences teaching K-12 students in a summer writing camp, creating vignettes based on writing camp experiences, and implementing those vignettes in teacher education settings. Analysis surfaced tensions between teacher and teacher educator identities and between stated objectives and implicit assumptions focused on multicultural education reform. Implications of teacher educators' sustained engagement in both K-12 and teacher preparation settings using the dual processes of reflection and action are discussed.
Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a ...large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward—an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.
A collaborative interdisciplinary systems biology framework is proposed to integrate physical and genetic interaction networks data along with genomics to inform insights into the neurobiology of disease that can then be translated to the clinic.
Altered neurological function will generally be behaviourally apparent. Many of the behavioural models pioneered in mammalian models are portable to zebrafish. Tests are available to capture ...alterations in basic motor function, changes associated with exteroceptive and interoceptive sensory cues, and alterations in learning and memory performance. Excepting some endpoints involving learning, behavioural tests can be carried out at 4
days post fertilization. Given larvae can be reared quickly and in large numbers, and that software solutions are readily available from multiple vendors to automatically test behavioural responses in 96 larvae simultaneously, zebrafish are a potent and rapid model for screening neurological impairments. Coupling current and emerging behavioural endpoints with molecular techniques will permit and accelerate the determination of the mechanisms behind neurotoxicity and degeneration, as well as provide numerous means to test remedial drugs and other therapies. The emphasis of this review is to highlight unexplored/underutilized behavioural assays for future studies. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.
►Neurotoxicity and neurodegeneration typically have associated behavioural phenotypes. ►Zebrafish behavioural assays have tight parallel with mammalian assays. ►Behavioural assays can test motor and sensory neuron function, and cognitive performance. ►Numerous behavioural assays can be conducted on zebrafish 4 days post fertilization
Viral vector technologies are commonly used in neuroscience research to understand and manipulate neural circuits, but successful applications of these technologies in non-human primate models have ...been inconsistent. An essential component to improve these technologies is an impartial and accurate assessment of the effectiveness of different viral constructs in the primate brain. We tested a diverse array of viral vectors delivered to the brain and extraocular muscles of macaques and compared three methods for histological assessment of viral-mediated fluorescent transgene expression: epifluorescence (Epi), immunofluorescence (IF), and immunohistochemistry (IHC). Importantly, IF and IHC identified a greater number of transduced neurons compared to Epi. Furthermore, IF and IHC reliably provided enhanced visualization of transgene in most cellular compartments (
, dendritic, axonal, and terminal fields), whereas the degree of labeling provided by Epi was inconsistent and predominantly restricted to somas and apical dendrites. Because Epi signals are unamplified (in contrast to IF and IHC), Epi may provide a more veridical assessment for the amount of accumulated transgene and, thus, the potential to chemogenetically or optogenetically manipulate neuronal activity. The comparatively weak Epi signals suggest that the current generations of viral constructs, regardless of delivered transgene, are not optimized for primates. This reinforces an emerging viewpoint that viral vectors tailored for the primate brain are necessary for basic research and human gene therapy.
In the United States (US), tuberculosis elimination strategies include scaling up latent tuberculosis infection (LTBI) diagnosis and treatment for persons at risk of progression to tuberculosis ...disease. The Massachusetts Department of Public Health partnered with Lynn Community Health Center to provide care to patients with LTBI who were born outside the US. The electronic health record was modified to facilitate collection of data elements for public health assessment of the LTBI care cascade. Among health center patients born outside the US, testing for tuberculosis infection increased by over 190%. From October 1, 2016 to March 21, 2019, 8827 patients were screened and 1368 (15.5%) were diagnosed with LTBI. Using the electronic health record, we documented treatment completion for 645/1368 (47.1%) patients. The greatest drop-offs occurred between testing for TB infection and clinical evaluation after a positive test (24.3%) and between the recommendation for LTBI treatment and completion of a treatment course (22.8%). Tuberculosis care delivery was embedded in the primary care medical home, bringing patient-centered care to those at high risk for loss to follow up. The partnership between public health and the community health center promoted quality improvement.
During an antisolvent crystallization process, micron-sized crystals of salicylic acid in the particle size range 20 to 150 μm were prepared under specific sets of crystallization conditions, with a ...focus on drug concentration, temperature, and solvent composition. For each experiment, the size outcome was determined by a number of knock on (often competing) influencing factors, including supersaturation, mass available for deposition during crystallization, and influence of temperature and solvent composition on crystallization kinetics. A certain fraction of the crystals, especially at higher solute concentration, developed a spectacular hollow shape with an almost perfect rectangular outer cross-section. A mechanistic explanation for the formation of hollow crystals is proposed. The use of additives during crystallization introduced further control over the size and, perhaps more noticeably, over the shape of the salicylic acid crystals. The lengths of salicylic acid crystals decreased to as low as 6 μm with increasing concentration of HPMC. Both HPMC and CMC induced a change in the crystal habit from square prisms (for the pure system) to needles, due to the structural ability of these additives to selectively attach through hydrogen bonding to the dominating 110 faces of the crystals and slow down growth in that direction. SDS exhibited less of an influence on the size, but due to its attachment to the 001 faces, it prevented indentation of these faces from occurring and thus prevented the formation of hollow crystals.
Submicron to small-micron-sized particles of the hydrophobic drug, fenofibrate, were prepared by controlled crystallization in order to influence its dissolution behavior. An antisolvent ...precipitation process successfully generated particles (200–300 nm) which matched the size and dissolution behavior of a commercial wet-milled formulation of the drug. Although the preparation of submicron-sized particles was straightforward, retaining their size in suspension and during isolation was a challenge. Additives were employed to temporarily stabilize the suspension, and extend the time window for isolation of the submicron particles. Precipitated particles were isolated primarily by immediate freeze–drying, but drying stresses were found to destabilize the fragile submicron system. The growth pathway of particles in suspension and during oven and freeze–drying were compared. Although the growth pathways appeared considerably different from a visual morphological perspective, an investigation of the electron diffraction patterns and the inner-particle surfaces showed that the growth pathways were the same: molecular addition by Ostwald ripening. The observed differences in the time-resolved particle morphologies were found to be a result of the freeze–drying process.
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