Molecular analysis of Mycobacterium tuberculosis DNA from a family of 18th century Hungarians

The naturally mummified remains of a mother and two daughters found in an 18th century Hungarian crypt were analysed, using multiple molecular genetic techniques to examine the epidemiology and evolution of tuberculosis. DNA was amplified from a number of targets on the Mycobacterium tuberculosis genome, including DNA from IS6110, gyrA, katG codon 463, oxyR, dnaA–dnaN, mtp40, plcD and the direct repeat (DR) region. The strains present in the mummified remains were identified as M. tuberculosis and not Mycobacterium bovis, from katG and gyrA genotyping, PCR from the oxyR and mtp40 loci, and spoligotyping. Spoligotyping divided the samples into two strain types, and screening for a deletion in the MT1801–plcD region initially divided the strains into three types. Further investigation showed, however, that an apparent deletion was due to poor DNA preservation. By comparing the effect of PCR target size on the yield of amplicon, a clear difference was shown between 18th century and modern M. tuberculosis DNA. A two-centre system was used to confirm the findings of this study, which clearly demonstrate the value of using molecular genetic techniques to study historical cases of tuberculosis and the care required in drawing conclusions. The genotyping and spoligotyping results are consistent with the most recent theory of the evolution and spread of the modern tuberculosis epidemic

The Equivalence Principle and the Constants of Nature

We briefly review the various contexts within which one might address the issue of ``why'' the dimensionless constants of Nature have the particular values that they are observed to have. Both the general historical trend, in physics, of replacing a-priori-given, absolute structures by dynamical entities, and anthropic considerations, suggest that coupling ``constants'' have a dynamical nature. This hints at the existence of observable violations of the Equivalence Principle at some level, and motivates the need for improved tests of the Equivalence Principle.Comment: 12 pages; invited talk at the ISSI Workshop on the Nature of Gravity: Confronting Theory and Experiment in Space, Bern, Switzerland, 6-10 October 2008; to appear in Space Science Review

Semileptonic and nonleptonic B decays to three charm quarks: B->J/psi (eta_c) D l nu and J/psi (eta_c) D pi

We evaluate the form factors describing the semileptonic decays $\bar{B^0}\to J/\psi (\eta_c) D^+ \ell^- \bar \nu_\ell$, within the framework of a QCD relativistic potential model. This decay is complementary to $\bar{B^0}\to J/\psi (\eta_c) D^+ \pi^-$ in a phase space region where a pion factors out.We estimate the branching ratio for these semileptonic and nonleptonic channels, finding $\mathcal{BR}(\bar{B^0} \to J/\psi (\eta_c) D^+ \ell \nu_\ell) \simeq 10^{-13}$, $\mathcal{BR}(\bar{B^0} \to J/\psi D^+ \pi^-) = 3.1 \times 10^{-8}$ and $\mathcal{BR}(\bar{B^0} \to \eta_c D^+ \pi^-) = 3.5 \times 10^{-8}$.Comment: 14 pages, 4 figure

Determination of the Strong Coupling \boldmath{\as} from hadronic Event Shapes and NNLO QCD predictions using JADE Data

Event Shape Data from $e^+e^-$ annihilation into hadrons collected by the JADE experiment at centre-of-mass energies between 14 GeV and 44 GeV are used to determine the strong coupling $\alpha_S$. QCD predictions complete to next-to-next-to-leading order (NNLO), alternatively combined with resummed next-to-leading-log-approximation (NNLO+NLLA) calculations, are used. The combined value from six different event shape observables at the six JADE centre-of-mass energies using the NNLO calculations is $\alpha_S(M_Z)$= 0.1210 +/- 0.0007(stat.) +/- 0.0021(expt.) +/- 0.0044(had.) +/- 0.0036(theo.) and with the NNLO+NLLA calculations the combined value is $\alpha_S$= 0.1172 +/- 0.0006(stat.) +/- 0.0020(expt.) +/- 0.0035(had.) +/- 0.0030(theo.) . The stability of the NNLO and NNLO+NLLA results with respect to missing higher order contributions, studied by variations of the renormalisation scale, is improved compared to previous results obtained with NLO+NLLA or with NLO predictions only. The observed energy dependence of $\alpha_S$ agrees with the QCD prediction of asymptotic freedom and excludes absence of running with 99% confidence level.Comment: 9 pages, EPHJA style, 4 figures, corresponds to published version with JADE author lis

Texture zeros for the standard model Quark mass matrices

ABSTRACT: A way of counting free parameters in the quark mass matrices of the standard model, including the constraints coming from weak basis transformations, is presented; this allow to understand the exact physical meaning of the parallel and non-parallel texture zeros which appear in some “ans¨atz” of the 3 × 3 quark mass matrices, including the CP violation phenomena in the analysis, it is shown why the six texture zeros are ruled out. Finally, a five texture zeros “ans¨atze”which properly copes with all experimental constrains, including the angles of the unitary triangle, is presented

Critical analysis: use of polymerase chain reaction to diagnose leprosy

ABSTRACT Leprosy is a neglected tropical disease and an important public health problem, especially in developing countries. It is a chronic infectious disease that is caused by Mycobacterium leprae, which has a predilection for the skin and peripheral nerves. Although it has low sensitivity, slit-skin smear (SSS) remains the conventional auxiliary laboratory technique for the clinical diagnosis of leprosy. Polymerase chain reaction (PCR) is a molecular biology technique that holds promise as a simple and sensitive diagnostic tool. In the present study, the performance of two PCR methods, using different targets, PCR-LP and PCR-P, were compared with SSS with regard to leprosy diagnosis in a reference laboratory. M. leprae DNA was extracted from 106 lymph samples of 40 patients who had clinical suspicion of leprosy. The samples were subjected to both PCR techniques and SSS. Amplification of the human b-globin gene was used as PCR inhibitor control. The specificity of both PCR techniques was 100%, and sensitivity was 0.007 and 0.015 µg/ml for PCR-LP and PCR-P, respectively. No significant difference was found between either the PCR-LP or PCR-P results and SSS results (p > 0.05). Although PCR is not yet a replacement for SSS in the diagnosis of leprosy, this technique may be used as an efficient auxiliary tool for early detection of the disease, especially in endemic regions. This strategy may also be useful in cases in which SSS results are negative (e.g., in paucibacillary patients) and cases in which skin biopsy cannot be performed

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations

Clustering identifies endotypes of traumatic brain injury in an intensive care cohort: a CENTER-TBI study

Background While the Glasgow coma scale (GCS) is one of the strongest outcome predictors, the current classification of traumatic brain injury (TBI) as ‘mild’, ‘moderate’ or ‘severe’ based on this fails to capture enormous heterogeneity in pathophysiology and treatment response. We hypothesized that data-driven characterization of TBI could identify distinct endotypes and give mechanistic insights. Methods We developed an unsupervised statistical clustering model based on a mixture of probabilistic graphs for presentation (< 24 h) demographic, clinical, physiological, laboratory and imaging data to identify subgroups of TBI patients admitted to the intensive care unit in the CENTER-TBI dataset (N = 1,728). A cluster similarity index was used for robust determination of optimal cluster number. Mutual information was used to quantify feature importance and for cluster interpretation. Results Six stable endotypes were identified with distinct GCS and composite systemic metabolic stress profiles, distinguished by GCS, blood lactate, oxygen saturation, serum creatinine, glucose, base excess, pH, arterial partial pressure of carbon dioxide, and body temperature. Notably, a cluster with ‘moderate’ TBI (by traditional classification) and deranged metabolic profile, had a worse outcome than a cluster with ‘severe’ GCS and a normal metabolic profile. Addition of cluster labels significantly improved the prognostic precision of the IMPACT (International Mission for Prognosis and Analysis of Clinical trials in TBI) extended model, for prediction of both unfavourable outcome and mortality (both p < 0.001). Conclusions Six stable and clinically distinct TBI endotypes were identified by probabilistic unsupervised clustering. In addition to presenting neurology, a profile of biochemical derangement was found to be an important distinguishing feature that was both biologically plausible and associated with outcome. Our work motivates refining current TBI classifications with factors describing metabolic stress. Such data-driven clusters suggest TBI endotypes that merit investigation to identify bespoke treatment strategies to improve care

Tracheal intubation in traumatic brain injury

Background: We aimed to study the associations between pre- and in-hospital tracheal intubation and outcomes in traumatic brain injury (TBI), and whether the association varied according to injury severity. Methods: Data from the international prospective pan-European cohort study, Collaborative European NeuroTrauma Effectiveness Research for TBI (CENTER-TBI), were used (n=4509). For prehospital intubation, we excluded self-presenters. For in-hospital intubation, patients whose tracheas were intubated on-scene were excluded. The association between intubation and outcome was analysed with ordinal regression with adjustment for the International Mission for Prognosis and Analysis of Clinical Trials in TBI variables and extracranial injury. We assessed whether the effect of intubation varied by injury severity by testing the added value of an interaction term with likelihood ratio tests. Results: In the prehospital analysis, 890/3736 (24%) patients had their tracheas intubated at scene. In the in-hospital analysis, 460/2930 (16%) patients had their tracheas intubated in the emergency department. There was no adjusted overall effect on functional outcome of prehospital intubation (odds ratio=1.01; 95% confidence interval, 0.79–1.28; P=0.96), and the adjusted overall effect of in-hospital intubation was not significant (odds ratio=0.86; 95% confidence interval, 0.65–1.13; P=0.28). However, prehospital intubation was associated with better functional outcome in patients with higher thorax and abdominal Abbreviated Injury Scale scores (P=0.009 and P=0.02, respectively), whereas in-hospital intubation was associated with better outcome in patients with lower Glasgow Coma Scale scores (P=0.01): in-hospital intubation was associated with better functional outcome in patients with Glasgow Coma Scale scores of 10 or lower. Conclusion: The benefits and harms of tracheal intubation should be carefully evaluated in patients with TBI to optimise benefit. This study suggests that extracranial injury should influence the decision in the prehospital setting, and level of consciousness in the in-hospital setting. Clinical trial registration: NCT02210221