Summary Background Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drug-susceptibility testing is slow and expensive, and commercial genotypic assays ...screen only common resistance-determining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all first-line and second-line drugs for tuberculosis. Methods Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identified from the drug-resistance scientific literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance. Findings We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI 90·7–93·7) and 98·4% specificity (98·1–98·7). 10·8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance determinants were identified among mutations under selection pressure in non-candidate genes. Interpretation A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. This approach could be integrated into routine diagnostic workflows, phasing out phenotypic drug-susceptibility testing while reporting drug resistance early. Funding Wellcome Trust, National Institute of Health Research, Medical Research Council, and the European Union.
Insufficient cardiac output in individuals with heart failure (HF) limits daily functioning and reduces quality of life. Although lower cerebral perfusion, secondary to limitations in cardiac output, ...has been observed during moderate-intensity efforts, individuals with HF also may be at risk for lower perfusion during even low-intensity ambulatory activities.
We determined whether HF is associated with an altered cerebrovascular response to low-intensity activities representative of typical challenges of daily living. In this study, we monitored central hemodynamics and middle cerebral blood velocity (MCAv) and cerebral tissue oxygenation (near-infrared spectroscopy) in 10 individuals with HF (aged 78 ± 4 years; left ventricular ejection fraction 20%-61%) and 13 similar-aged controls (79 ± 8 years; 52%–73%) during 3 randomized transitions, as follows: (i) supine-to-standing; (ii) sitting-to-slow-paced over-ground walking; and (iii) sitting-to-normal-paced over-ground walking.
Throughout supine, sitting, standing, and both walking conditions, individuals with HF had lower cardiac index and cerebral tissue oxygenation than controls (P < 0.05), and MCAv was lower across the range of blood pressure in HF patients (P = 0.051) and during walking only (P = 0.011). Individuals with HF had an attenuated increase in stroke volume index and cardiac index during normal-paced walking, compared to controls (P < 0.01).
The indices of cerebral perfusion from MCAv and cerebral oxygenation were lower during ambulatory activities in individuals with HF; however, relationships between MCAv and blood pressure were not different between those with HF and controls, indicating no difference in static cerebral autoregulation.
Un débit cardiaque insuffisant chez les personnes atteintes d’insuffisance cardiaque limite les activités quotidiennes et affecte la qualité de vie. Par exemple, des efforts d’intensité modérée ont été associés à une perfusion cérébrale affaiblie chez ces personnes. Or, il semble que même des activités ambulatoires de faible intensité soient susceptibles d’avoir les mêmes conséquences.
Nous voulions déterminer si l’insuffisance cardiaque est associée à une altération de la réponse cérébrovasculaire à des activités de faible intensité qui sont typiques de la vie quotidienne. Dans le cadre de cette étude, nous avons surveillé l’hémodynamique centrale et la vitesse du sang dans l’artère cérébrale moyenne (VACM), ainsi que l’oxygénation tissulaire cérébrale (par spectroscopie dans le proche infrarouge) chez 10 personnes atteintes d’insuffisance cardiaque (âge : 78 ± 4 ans; fraction d’éjection du ventricule gauche de 20 à 61 %) et 13 témoins d’âge similaire (79 ± 8 ans; de 52 à 73 %) lors de 3 transitions réparties de façon aléatoire, soit : i) de la position couchée à debout; ii) de la position assise à une marche lente et iii) de la position couchée à une marche à vitesse normale.
En position couchée, assise ou debout et avec les deux vitesses de marche, l’index cardiaque et l’oxygénation tissulaire cérébrale étaient plus faibles chez les personnes atteintes d’insuffisance cardiaque que chez les témoins (p < 0,05); la VACM était plus faible dans toutes les plages de tension artérielle chez les personnes atteintes d’insuffisance cardiaque (p = 0,051) et durant la marche seulement (p = 0,011). Les personnes atteintes d’insuffisance cardiaque présentaient une plus faible augmentation du volume d’éjection systolique et de l’index cardiaque durant la marche à vitesse normale, comparativement aux témoins (p < 0,01).
Les indices de la perfusion cérébrale selon la VACM et l’oxygénation cérébrale étaient réduits durant les activités ambulatoires chez les personnes atteintes d’insuffisance cardiaque; cependant, les relations entre la VACM et la tension artérielle n’étaient pas différentes entre les personnes atteintes d’insuffisance cardiaque et les témoins, ce qui indique que l’autorégulation cérébrale statique n’est pas un facteur de différenciation.
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