The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and ...containment strategies.
In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179).
Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid.
More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing.
UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology.
To develop an effective and sustainable cell therapy for sickle cell disease (SCD), we investigated the feasibility of targeted disruption of the
gene, either within exon 2 or at the GATAA motif in ...the intronic erythroid-specific enhancer, using zinc finger nucleases in human bone marrow (BM) CD34
hematopoietic stem and progenitor cells (HSPCs). Both targeting strategies upregulated fetal globin expression in erythroid cells to levels predicted to inhibit hemoglobin S polymerization. However, complete inactivation of
resulting from bi-allelic frameshift mutations in
exon 2 adversely affected erythroid enucleation. In contrast, bi-allelic disruption of the GATAA motif in the erythroid enhancer of
did not negatively impact enucleation. Furthermore,
exon 2-edited BM-CD34
cells demonstrated a significantly reduced engraftment potential in immunodeficient mice. Such an adverse effect on HSPC function was not observed upon
erythroid-enhancer GATAA motif editing, because enhancer-edited CD34
cells achieved robust long-term engraftment and gave rise to erythroid cells with elevated levels of fetal globin expression when chimeric BM was cultured ex vivo. Altogether, our results support further clinical development of the
erythroid-specific enhancer editing in BM-CD34
HSPCs as an autologous stem cell therapy in SCD patients.
Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods ...The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.
The whole-genome duplication 80 million years ago of the common ancestor of salmonids (salmonid-specific fourth vertebrate whole-genome duplication, Ss4R) provides unique opportunities to learn about ...the evolutionary fate of a duplicated vertebrate genome in 70 extant lineages. Here we present a high-quality genome assembly for Atlantic salmon (Salmo salar), and show that large genomic reorganizations, coinciding with bursts of transposon-mediated repeat expansions, were crucial for the post-Ss4R rediploidization process. Comparisons of duplicate gene expression patterns across a wide range of tissues with orthologous genes from a pre-Ss4R outgroup unexpectedly demonstrate far more instances of neofunctionalization than subfunctionalization. Surprisingly, we find that genes that were retained as duplicates after the teleost-specific whole-genome duplication 320 million years ago were not more likely to be retained after the Ss4R, and that the duplicate retention was not influenced to a great extent by the nature of the predicted protein interactions of the gene products. Finally, we demonstrate that the Atlantic salmon assembly can serve as a reference sequence for the study of other salmonids for a range of purposes.
Tafenoquine (TQ) is an 8-aminoquinoline (8AQ) that has been tested in several Phase II and Phase III clinical studies and is currently in late stage development as an anti-malarial prophylactic ...agent. NPC-1161B is a promising 8AQ in late preclinical development. It has recently been reported that the 8AQ drug primaquine requires metabolic activation by CYP 2D6 for efficacy in humans and in mice, highlighting the importance of pharmacogenomics in the target population when administering primaquine. A logical follow-up study was to determine whether CYP 2D activation is required for other compounds in the 8AQ structural class.
In the present study, the anti-malarial activities of NPC-1161B and TQ were assessed against luciferase expressing Plasmodium berghei in CYP 2D knock-out mice in comparison with normal C57BL/6 mice (WT) and with humanized/CYP 2D6 knock-in mice by monitoring luminescence with an in vivo imaging system. These experiments were designed to determine the direct effects of CYP 2D metabolic activation on the anti-malarial efficacy of NPC-1161B and TQ.
NPC-1161B and TQ exhibited no anti-malarial activity in CYP 2D knock-out mice when dosed at their ED100 values (1 mg/kg and 3 mg/kg, respectively) established in WT mice. TQ anti-malarial activity was partially restored in humanized/CYP 2D6 knock-in mice when tested at two times its ED100.
The results reported here strongly suggest that metabolism of NPC-1161B and TQ by the CYP 2D enzyme class is essential for their anti-malarial activity. Furthermore, these results may provide a possible explanation for therapeutic failures for patients who do not respond to 8AQ treatment for relapsing malaria. Because CYP 2D6 is highly polymorphic, variable expression of this enzyme in humans represents a significant pharmacogenomic liability for 8AQs which require CYP 2D metabolic activation for efficacy, particularly for large-scale prophylaxis and eradication campaigns.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Effective interventions to prevent diagnostic error among critically ill children should be informed by diagnostic error prevalence and etiologies. We aimed to determine the prevalence and ...characteristics of diagnostic errors and identify factors associated with error in patients admitted to the PICU.
Multicenter retrospective cohort study using structured medical record review by trained clinicians using the Revised Safer Dx instrument to identify diagnostic error (defined as missed opportunities in diagnosis). Cases with potential errors were further reviewed by four pediatric intensivists who made final consensus determinations of diagnostic error occurrence. Demographic, clinical, clinician, and encounter data were also collected.
Four academic tertiary-referral PICUs.
Eight hundred eighty-two randomly selected patients 0-18 years old who were nonelectively admitted to participating PICUs.
None.
Of 882 patient admissions, 13 (1.5%) had a diagnostic error up to 7 days after PICU admission. Infections (46%) and respiratory conditions (23%) were the most common missed diagnoses. One diagnostic error caused harm with a prolonged hospital stay. Common missed diagnostic opportunities included failure to consider the diagnosis despite a suggestive history (69%) and failure to broaden diagnostic testing (69%). Unadjusted analysis identified more diagnostic errors in patients with atypical presentations (23.1% vs 3.6%, p = 0.011), neurologic chief complaints (46.2% vs 18.8%, p = 0.024), admitting intensivists greater than or equal to 45 years old (92.3% vs 65.1%, p = 0.042), admitting intensivists with more service weeks/year (mean 12.8 vs 10.9 wk, p = 0.031), and diagnostic uncertainty on admission (77% vs 25.1%, p < 0.001). Generalized linear mixed models determined that atypical presentation (odds ratio OR 4.58; 95% CI, 0.94-17.1) and diagnostic uncertainty on admission (OR 9.67; 95% CI, 2.86-44.0) were significantly associated with diagnostic error.
Among critically ill children, 1.5% had a diagnostic error up to 7 days after PICU admission. Diagnostic errors were associated with atypical presentations and diagnostic uncertainty on admission, suggesting possible targets for intervention.
selection of remdesivir-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed the emergence of a V166L substitution, located outside of the polymerase active site of the ...Nsp12 protein, after 9 passages of a single lineage. V166L remained the only Nsp12 substitution after 17 passages (10 μM remdesivir), conferring a 2.3-fold increase in 50% effective concentration (EC
). When V166L was introduced into a recombinant SARS-CoV-2 virus, a 1.5-fold increase in EC
was observed, indicating a high
barrier to remdesivir resistance.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
Submitted 6 March 2006
; accepted in final form 26 September 2006
Obstructive ...sleep apnea is caused by pharyngeal occlusion due to alterations in upper airway mechanical properties and/or disturbances in neuromuscular control. The objective of the study was to determine the relative contribution of mechanical loads and dynamic neuromuscular responses to pharyngeal collapse during sleep. Sixteen obstructive sleep apnea patients and sixteen normal subjects were matched on age, sex, and body mass index. Pharyngeal collapsibility, defined by the critical pressure, was measured during sleep. The critical pressure was partitioned between its passive mechanical properties (passive critical pressure) and active dynamic responses to upper airway obstruction (active critical pressure). Compared with normal subjects, sleep apnea patients demonstrated elevated mechanical loads as demonstrated by higher passive critical pressures 0.05 (SD 2.4) vs. 4.5 cmH 2 O (SD 3.0), P = 0.0003. Dynamic responses were depressed in sleep apnea patients, as suggested by failure to lower their active critical pressures 1.6 (SD 3.5) vs. 11.1 cmH 2 O (SD 5.3), P < 0.0001 in response to upper airway obstruction. Moreover, elevated mechanical loads placed some normal individuals at risk for sleep apnea. In this subset, dynamic responses to upper airway obstruction compensated for mechanical loads and maintained airway patency by lowering the active critical pressure. The present study suggests that increased mechanical loads and blunted neuromuscular responses are both required for the development of obstructive sleep apnea.
obstructive sleep apnea; critical pressure; mechanical properties; neuromuscular control
Address for reprint requests and other correspondence: S. P. Patil, Johns Hopkins Sleep Disorders Center, Asthma and Allergy Bldg., 5501 Hopkins Bayview Circle, Rm. 4B30A, Baltimore, MD 21224 (e-mail: spatil{at}jhmi.edu )
We present total and polarized intensity images of 15 active galactic nuclei obtained with the Very Long Baseline Array at 7 mm wavelength at 17 epochs from 1998 March to 2001 April. At some epochs ...the images are accompanied by nearly simultaneous polarization measurements at 3 mm, 1.35/0.85 mm, and optical wavelengths. Here we analyze the 7 mm images to define the properties of the jets of two radio galaxies, five BL Lac objects, and eight quasars on angular scales 0.1 mas. We determine the apparent velocities of 106 features in the jets. For many of the features we derive Doppler factors using a new method based on a comparison of the timescale of decline in flux density with the light-travel time across the emitting region. This allows us to estimate the Lorentz factors (), intrinsic brightness temperatures, and viewing angles of 73 superluminal knots, as well as the opening angle of the jet for each source. The Lorentz factors of the jet flows in the different blazars range from ~ 5 to 40 with the majority of the quasar components having ~ 16-18, while the values in the BL Lac objects are more uniformly distributed. The brightest knots in the quasars have the highest apparent speeds, while the more slowly moving components are pronounced in the BL Lac objects. The quasars in our sample have similar opening angles and marginally smaller viewing angles than the BL Lacs. The two radio galaxies have lower Lorentz factors and wider viewing angles than the blazars. Opening angle and Lorentz factor are inversely proportional, as predicted by gasdynamical models. The brightness temperature drops more abruptly with distance from the core in the BL Lac objects than in the quasars and radio galaxies, perhaps owing to stronger magnetic fields in the former resulting in more severe synchrotron losses of the highest energy electrons. In nine sources we detect statistically meaningful deviations from ballistic motion, with the majority of components accelerating with distance from the core. In six sources we identify jet features with characteristics of trailing shocks that form behind the primary strong perturbations in jet simulations. The apparent speeds of these components increase with distance from the core, suggestive of acceleration of the underlying jet.
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