Extending outbreak investigation with machine learning and graph theory: Benefits of new tools with application to a nosocomial outbreak of a multidrug-resistant organism.

OBJECTIVE From January 1, 2018, until July 31, 2020, our hospital network experienced an outbreak of vancomycin-resistant enterococci (VRE). The goal of our study was to improve existing processes by applying machine-learning and graph-theoretical methods to a nosocomial outbreak investigation. METHODS We assembled medical records generated during the first 2 years of the outbreak period (January 2018 through December 2019). We identified risk factors for VRE colonization using standard statistical methods, and we extended these with a decision-tree machine-learning approach. We then elicited possible transmission pathways by detecting commonalities between VRE cases using a graph theoretical network analysis approach. RESULTS We compared 560 VRE patients to 86,684 controls. Logistic models revealed predictors of VRE colonization as age (aOR, 1.4 (per 10 years), with 95% confidence interval [CI], 1.3-1.5; P < .001), ICU admission during stay (aOR, 1.5; 95% CI, 1.2-1.9; P < .001), Charlson comorbidity score (aOR, 1.1; 95% CI, 1.1-1.2; P < .001), the number of different prescribed antibiotics (aOR, 1.6; 95% CI, 1.5-1.7; P < .001), and the number of rooms the patient stayed in during their hospitalization(s) (aOR, 1.1; 95% CI, 1.1-1.2; P < .001). The decision-tree machine-learning method confirmed these findings. Graph network analysis established 3 main pathways by which the VRE cases were connected: healthcare personnel, medical devices, and patient rooms. CONCLUSIONS We identified risk factors for being a VRE carrier, along with 3 important links with VRE (healthcare personnel, medical devices, patient rooms). Data science is likely to provide a better understanding of outbreaks, but interpretations require data maturity, and potential confounding factors must be considered

Noninvasive diffusion magnetic resonance imaging of brain tumour cell size for the early detection of therapeutic response

Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure. Here, diffusion MRI data were acquired in a GL261 glioma mouse model before and during treatment with Temozolomide. The biophysical model VERDICT (Vascular Extracellular and Restricted Diffusion for Cytometry in Tumours) was applied to the MRI data to quantify multi-compartmental parameters connected to the underlying tissue microstructure, which could potentially be useful clinical biomarkers. These parameters were compared to ADC and kurtosis diffusion models, and, measures from histology and optical projection tomography. MRI data was also acquired in patients to assess the feasibility of applying VERDICT in a range of different glioma subtypes. In the GL261 gliomas, cellular changes were detected according to the VERDICT model in advance of gross tumour volume changes as well as ADC and kurtosis models. VERDICT parameters in glioblastoma patients were most consistent with the GL261 mouse model, whilst displaying additional regions of localised tissue heterogeneity. The present VERDICT model was less appropriate for modelling more diffuse astrocytomas and oligodendrogliomas, but could be tuned to improve the representation of these tumour types. Biophysical modelling of the diffusion MRI signal permits monitoring of brain tumours without invasive intervention. VERDICT responds to microstructural changes induced by chemotherapy, is feasible within clinical scan times and could provide useful biomarkers of treatment response

siRNA Targeted to p53 Attenuates Ischemic and Cisplatin-Induced Acute Kidney Injury

Proximal tubule cells (PTCs), which are the primary site of kidney injury associated with ischemia or nephrotoxicity, are the site of oligonucleotide reabsorption within the kidney. We exploited this property to test the efficacy of siRNA targeted to p53, a pivotal protein in the apoptotic pathway, to prevent kidney injury. Naked synthetic siRNA to p53 injected intravenously 4 h after ischemic injury maximally protected both PTCs and kidney function. PTCs were the primary site for siRNA uptake within the kidney and body. Following glomerular filtration, endocytic uptake of Cy3-siRNA by PTCs was rapid and extensive, and significantly reduced ischemia-induced p53 upregulation. The duration of the siRNA effect in PTCs was 24 to 48 h, determined by levels of p53 mRNA and protein expression. Both Cy3 fluorescence and in situ hybridization of siRNA corroborated a short t½ for siRNA. The extent of renoprotection, decrease in cellular p53 and attenuation of p53-mediated apoptosis by siRNA were dose- and time-dependent. Analysis of renal histology and apoptosis revealed improved injury scores in both cortical and corticomedullary regions. siRNA to p53 was also effective in a model of cisplatin-induced kidney injury. Taken together, these data indicate that rapid delivery of siRNA to proximal tubule cells follows intravenous administration. Targeting siRNA to p53 leads to a dose-dependent attenuation of apoptotic signaling, suggesting potential therapeutic benefit for ischemic and nephrotoxic kidney injury

Hydrodynamic Isotonic Fluid Delivery Ameliorates Moderate-to-Severe Ischemia-Reperfusion Injury in Rat Kidneys

Highly aerobic organs like the kidney are innately susceptible to ischemia-reperfusion (I/R) injury, which can originate from sources including myocardial infarction, renal trauma, and transplant. Therapy is mainly supportive and depends on the cause(s) of damage. In the absence of hypervolemia, intravenous fluid delivery is frequently the first course of treatment but does not reverse established AKI. Evidence suggests that disrupting leukocyte adhesion may prevent the impairment of renal microvascular perfusion and the heightened inflammatory response that exacerbate ischemic renal injury. We investigated the therapeutic potential of hydrodynamic isotonic fluid delivery (HIFD) to the left renal vein 24 hours after inducing moderate-to-severe unilateral IRI in rats. HIFD significantly increased hydrostatic pressure within the renal vein. When conducted after established AKI, 24 hours after I/R injury, HIFD produced substantial and statistically significant decreases in serum creatinine levels compared with levels in animals given an equivalent volume of saline via peripheral infusion (P<0.05). Intravital confocal microscopy performed immediately after HIFD showed improved microvascular perfusion. Notably, HIFD also resulted in immediate enhancement of parenchymal labeling with the fluorescent dye Hoechst 33342. HIFD also associated with a significant reduction in the accumulation of renal leukocytes, including proinflammatory T cells. Additionally, HIFD significantly reduced peritubular capillary erythrocyte congestion and improved histologic scores of tubular injury 4 days after IRI. Taken together, these results indicate that HIFD performed after establishment of AKI rapidly restores microvascular perfusion and small molecule accessibility, with improvement in overall renal function

Heavy- to light-meson transition form factors

Semileptonic heavy -> heavy and heavy -> light meson transitions are studied as a phenomenological application of a heavy-quark limit of Dyson-Schwinger equations. Employing two parameters: E, the difference between the mass of the heavy meson and the effective-mass of the heavy quark; and Lambda, the width of the heavy-meson Bethe-Salpeter amplitude, we calculate f_+(t) for all decays on their entire kinematically accessible t-domain. Our study favours f_B in the range 0.135-0.17 GeV and with E=0.44 GeV and 1/Lambda = 0.14 fm we obtain f_+^{B pi}(0) = 0.46. As a result of neglecting 1/m_c-corrections, we estimate that our calculated values of \rho^2 = 0.87 and f_+^{DK}(0)=0.62 are too low by approximately 15%. However, the bulk of these corrections should cancel in our calculated values of Br(D -> \pi l nu)/Br(D -> K l nu)=0.13 and f_+^{D pi}(0)/f_+^{DK}(0) = 1.16.Comment: 26 pages, 3 figures, REVTE

Infinitely many conservation laws for the discrete KdV equation

In \cite{RH3} Rasin and Hydon suggested a way to construct an infinite number of conservation laws for the discrete KdV equation (dKdV), by repeated application of a certain symmetry to a known conservation law. It was not decided, however, whether the resulting conservation laws were distinct and nontrivial. In this paper we obtain the following results: (1) We give an alternative method to construct an infinite number of conservation laws using a discrete version of the Gardner transformation. (2) We give a direct proof that the Rasin-Hydon conservation laws are indeed distinct and nontrivial. (3) We consider a continuum limit in which the dKdV equation becomes a first-order eikonal equation. In this limit the two sets of conservation laws become the same, and are evidently distinct and nontrivial. This proves the nontriviality of the conservation laws constructed by the Gardner method, and gives an alternate proof of the nontriviality of the conservation laws constructed by the Rasin-Hydon method

Estimating the burden of iron deficiency among African children.

BACKGROUND: Iron deficiency (ID) is a major public health burden in African children and accurate prevalence estimates are important for effective nutritional interventions. However, ID may be incorrectly estimated in Africa because most measures of iron status are altered by inflammation and infections such as malaria. Through the current study, we have assessed different approaches to the prediction of iron status and estimated the burden of ID in African children. METHODS: We assayed iron and inflammatory biomarkers in 4853 children aged 0-8?years from Kenya, Uganda, Burkina Faso, South Africa, and The Gambia. We described iron status and its relationship with age, sex, inflammation, and malaria parasitemia. We defined ID using the WHO guideline (ferritin <?12??g/L or <?30??g/L in the presence of inflammation in children <?5?years old or <?15??g/L in children ??5?years old). We compared this with a recently proposed gold standard, which uses regression-correction for ferritin levels based on the relationship between ferritin levels, inflammatory markers, and malaria. We further investigated the utility of other iron biomarkers in predicting ID using the inflammation and malaria regression-corrected estimate as a gold standard. RESULTS: The prevalence of ID was highest at 1 year of age and in male infants. Inflammation and malaria parasitemia were associated with all iron biomarkers, although transferrin saturation was least affected. Overall prevalence of WHO-defined ID was 34% compared to 52% using the inflammation and malaria regression-corrected estimate. This unidentified burden of ID increased with age and was highest in countries with high prevalence of inflammation and malaria, where up to a quarter of iron-deficient children were misclassified as iron replete. Transferrin saturation <?11% most closely predicted the prevalence of ID according to the regression-correction gold standard. CONCLUSIONS: The prevalence of ID is underestimated in African children when defined using the WHO guidelines, especially in malaria-endemic populations, and the use of transferrin saturation may provide a more accurate approach. Further research is needed to identify the most accurate measures for determining the prevalence of ID in sub-Saharan Africa

Gravitational Lensing by Black Holes

We review the theoretical aspects of gravitational lensing by black holes, and discuss the perspectives for realistic observations. We will first treat lensing by spherically symmetric black holes, in which the formation of infinite sequences of higher order images emerges in the clearest way. We will then consider the effects of the spin of the black hole, with the formation of giant higher order caustics and multiple images. Finally, we will consider the perspectives for observations of black hole lensing, from the detection of secondary images of stellar sources and spots on the accretion disk to the interpretation of iron K-lines and direct imaging of the shadow of the black hole.Comment: Invited article for the GRG special issue on lensing (P. Jetzer, Y. Mellier and V. Perlick Eds.). 31 pages, 12 figure

Exotic ρ±ρ0\rho^\pm\rho^0 state photoproduction

It is shown that the list of unusual mesons planned for a careful study in photoproduction can be extended by the exotic states $X^\pm(1600)$ with $I^G(J ^{PC})=2^+(2^{++})$ which should be looked for in the $\rho^\pm\rho^0$ decay channels in the reactions $\gamma N\to\rho^\pm\rho^0N$ and $\gamma N\to\rho^\pm \rho^0\Delta$. The full classification of the $\rho^\pm\rho^0$ states by their quantum numbers is presented. A simple model for the spin structure of the $\gamma p\to f_2(1270)p$, $\gamma p\to a^0_2(1320)p$, and $\gamma N\to X^\pm (N, \Delta)$ reaction amplitudes is formulated and the tentative estimates of the corresponding cross sections at the incident photon energy $E_\gamma\approx 6$ GeV are obtained: $\sigma(\gamma p\to f_2(1270)p)\approx0.12$ $\mu$b, $\sigma(\gamma p\to a^0_2(1320)p)\approx0.25$ $\mu$b, $\sigma(\gamma N\to X^\pm N\to\rho^\pm\rho^0N)\approx0.018$ $\mu$b, and $\sigma(\gamma p\to X^-\Delta^{++ }\to\rho^-\rho^0\Delta^{++})\approx0.031$ $\mu$b. The problem of the $X^\pm$ signal extraction from the natural background due to the other $\pi^\pm\pi^0 \pi^+\pi^-$ production channels is discussed. In particular the estimates are presented for the $\gamma p\to h_1(1170)\pi^+n$, $\gamma p\to\rho'^{+}n\to \pi^+\pi^0\pi^+\pi^-n$, and $\gamma p\to\omega\rho^0p$ reaction cross sections. Our main conclusion is that the search for the exotic $X^\pm(2^+(2^{++}))$ states is quite feasible at JEFLAB facility. The expected yield of the $\gamma N\to X^\pm N\to\rho^\pm\rho^0N$ events in a 30-day run at the 100% detection efficiency approximates $2.8\times10^6$ events.Comment: 19 pages, revtex, 1 figure in postscipt, some comments and references added, a few minor typos corrected, to be published in Phys. Rev.