15 research outputs found
Retrospective observational study to assess the clinical management and outcomes of hospitalised patients with complicated urinary tract infection in countries with high prevalence of multidrug resistant Gram-negative bacteria (RESCUING)
INTRODUCTION: The emergence of multidrug resistant (MDR) Gram-negative bacteria (GNB), including carbapenemase-producing strains, has become a major therapeutic challenge. These MDR isolates are often involved in complicated urinary tract infection (cUTI), and are associated with poor clinical outcomes. The study has been designed to gain insight into the epidemiology, clinical management, outcome and healthcare cost of patients with cUTI, especially in countries with high prevalence of MDR GNB.
METHODS AND ANALYSIS: This multinational and multicentre observational, retrospective study will identify cases from 1 January 2013 to 31 December 2014 in order to collect data on patients with cUTI as a cause of hospital admission, and patients who develop cUTI during their hospital stay. The primary end point will be treatment failure defined as the presence of any of the following criteria: (1) signs or symptoms of cUTI present at diagnosis that have not improved by days 5â7 with appropriate antibiotic therapy, (2) new cUTI-related symptoms that have developed within 30â
days of diagnosis, (3) urine culture taken within 30â
days of diagnosis, either during or after completion of therapy, that grows â„104 colony-forming unit/mL of the original pathogen and (4) death irrespective of cause within 30â
days of the cUTI diagnosis.
SAMPLE SIZE: 1000 patients afford a power of 0.83 (α=0.05) to detect an absolute difference of 10% in the treatment failure rate between MDR bacteria and other pathogens. This should allow for the introduction of about 20 independent risk factors (or their interaction) in a logistic regression model looking at risk factors for failure.
ETHICS AND DISSEMINATION: Approval will be sought from all relevant Research Ethics Committees. Publication of this study will be considered as a joint publication by the participating investigator leads, and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE)
Cost of hospitalised patients due to complicated urinary tract infections: a retrospective observational study in countries with high prevalence of multidrug-resistant Gram-negative bacteria: the COMBACTE-MAGNET, RESCUING study
OBJECTIVE: Complicated urinary tract infections (cUTIs) impose a high burden on healthcare systems and are a frequent cause of hospitalisation. The aims of this paper are to estimate the cost per episode of patients hospitalised due to cUTI and to explore the factors associated with cUTI-related healthcare costs in eight countries with high prevalence of multidrug resistance (MDR). DESIGN: This is a multinational observational, retrospective study. The mean cost per episode was computed by multiplying the volume of healthcare use for each patient by the unit cost of each item of care and summing across all components. Costs were measured from the hospital perspective. Patient-level regression analyses were used to identify the factors explaining variation in cUTI-related costs. SETTING: The study was conducted in 20 hospitals in eight countries with high prevalence of multidrug resistant Gram-negative bacteria (Bulgaria, Greece, Hungary, Israel, Italy, Romania, Spain and Turkey). PARTICIPANTS: Data were obtained from 644 episodes of patients hospitalised due to cUTI. RESULTS: The mean cost per case was âŹ5700, with considerable variation between countries (largest value âŹ7740 in Turkey; lowest value âŹ4028 in Israel), mainly due to differences in length of hospital stay. Factors associated with higher costs per patient were: type of admission, infection source, infection severity, the Charlson comorbidity index and presence of MDR. CONCLUSIONS: The mean cost per hospitalised case of cUTI was substantial and varied significantly between countries. A better knowledge of the reasons for variations in length of stays could facilitate a better standardised quality of care for patients with cUTI and allow a more efficient allocation of healthcare resources. Urgent admissions, infections due to an indwelling urinary catheterisation, resulting in septic shock or severe sepsis, in patients with comorbidities and presenting MDR were related to a higher cost
Risk factors for treatment failure and mortality among hospitalized patients with complicated urinary tract infection: A multicenter retrospective cohort study (RESCUING study group)
Background. Complicated urinary tract infections (cUTIs) are responsible for a major share of all antibiotic consumption in hospitals. We aim to describe risk factors for treatment failure and mortality among patients with cUTIs. Methods. A multinational, multicentre retrospective cohort study, conducted in 20 countries in Europe and the Middle East. Data were collected from patients' files on hospitalised patients with a diagnosis of cUTI during 2013-2014. Primary outcome was treatment failure, secondary outcomes included 30 days all-cause mortality,among other outcomes. Multivariable analysis using a logistic model and the hospital as a random variable was performed to identify independent predictors for these outcomes. Results. A total of 981 patients with cUTI were included. Treatment failure was observed in 26.6% (261/981), all cause 30-day mortality rate was 8.7% (85/976), most of these in patients with catheter related UTI (CaUTI). Risk factors for treatment failure in multivariable analysis were ICU admission (OR 5.07, 95% CI 3.18-8.07), septic shock (OR 1.92, 95% CI 0.93-3.98), corticosteroid treatment (OR 1.92, 95% CI 1.12-3.54), bedridden (OR 2.11, 95%CI 1.4-3.18), older age (OR 1.02, 95% CI 1.0071.03-), metastatic cancer (OR 2.89, 95% CI 1.46-5.73) and CaUTI (OR 1.48, 95% CI 1.04-2.11). Management variables, such as inappropriate empirical antibiotic treatment or days to starting antibiotics were not associated with treatment failure or 30-day mortality. More patients with pyelonephritis were given appropriate empirical antibiotic therapy than other CaUTI [110/171; 64.3% vs. 116/270; 43%, p <0.005], nevertheless, this afforded no advantage in treatment failure rates nor mortality in these patients. Conclusions. In patients with cUTI we found no benefit of early appropriate empirical treatment on survival rates or other outcomes. Physicians might consider supportive treatment and watchful waiting in stable patients until the causative pathogen is defined
First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors
urpose
Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions.
Patients and Methods
Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST.
Results
Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10.
Conclusion
Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker
First-in-human phase I study of Atu027, a liposomal small interfering RNA formulation, targeting protein kinase N3 (PKN3) in patients with advanced solid tumors.
Peptide model XXVIII: An exploratory ab initio and density functional study on the side-chain-backbone interaction in N-acetyl-L-cysteine-N-methylamide and N-formyl-L-cysteinamide in their ÎłL-backbone conformations
A conformational and electronic study on the energetically preferred conformations (ÎłL) of N- and C-protected L-cysteine (P-CONH-CH(CH2SH)-CONH-Q, where P and Q may be H or Me) was carried out. After restraining the backbone (BB) conformation to its global minimum (ÎłL or C7eq), all nine possible side-chain (SC) conformations were subjected to geometry optimization at the HF/3-21G and the B3LYP/6-31G(d,p) levels of theory. Seven of the nine side-chain conformers were located on the potential-energy surface. All conformers were subjected to an AIM (atoms in molecules) analysis. This study indicates that three of the seven optimized conformers exhibited either or both SC â BB- or BB â SC-type intramolecular hydrogen bonding. Five conformers, however, had distances between a proton and a heteroatom that suggested hydrogen bonding.Fil: Zamora, Miguel Angel. Universidad Nacional de San Luis. Facultad de QuĂmica, BioquĂmica y Farmacia; ArgentinaFil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - San Luis. Instituto de MatemĂĄtica Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias FĂsico, MatemĂĄticas y Naturales. Instituto de MatemĂĄtica Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Rodriguez, Ana Maria. Universidad Nacional de San Luis. Facultad de QuĂmica, BioquĂmica y Farmacia; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones BiolĂłgicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias FĂsico MatemĂĄticas y Naturales. Instituto Multidisciplinario de Investigaciones BiolĂłgicas de San Luis; ArgentinaFil: Sosa, Carlos P.. Cray Inc.; Estados UnidosFil: Perczel, AndrĂĄs. Eötvös University; HungrĂaFil: Kucsman, ĂrpĂĄd. Eötvös University; HungrĂaFil: Farkas, Ădön. Eötvös University; HungrĂaFil: Deretey, Eugen. University of Toronto; CanadĂĄFil: Vank, Judith C.. University of Toronto; CanadĂĄFil: Csizmadia, Imre Gyula. University of Toronto; Canad
A comparison of bulk-sensitive spectroscopic probes of Yb valence in Kondo systems
We exploited complementary synchrotron radiation spectroscopies to study the Yb 4f electronic configuration
in three representative intermediate-valence materials: YbAl3, YbInCu4, and YbCu2Si2. High-resolution
x-ray absorption PFY-XAS, resonant inelastic x-ray scattering RIXS, and hard-x-ray photoemission HAXPES
data all show characteristic temperature-dependent changes of the Yb valence. For each material, the
increments measured from low 20 K to high 300 K temperature by the different probes are quite similar.
The estimated RIXS and XAS valences are consistently higher than the HAXPES values. We briefly discuss
the possible origin of this discrepancy
Risk factors and prognosis of complicated urinary tract infections caused by Pseudomonas aeruginosa in hospitalized patients: a retrospective multicenter cohort study
Aina Gomila,1,2 J Carratalà,1–3 N Eliakim-Raz,4 E Shaw,1,2 I Wiegand,5 L Vallejo-Torres,6 A Gorostiza,2 JM Vigo,7 S Morris,6 M Stoddart,8 S Grier,8 C Vank,5 N Cuperus,9 L Van den Heuvel,9 C Vuong,5 A MacGowan,8 L Leibovici,4 I Addy,5 M Pujol1,2 On behalf of COMBACTE MAGNET WP5 RESCUING Study Group and Study Sites 1Department of Infectious Diseases, Hospital Universitari de Bellvitge, Institut Català de la Salut (ICS-HUB), Spanish Network for Research in Infectious Diseases (REIPI RD12/0015), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; 2Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain; 3Infectious Diseases Department, University of Barcelona, Barcelona, Spain; 4Department of Medicine E, Beilinson Hospital, Rabin Medical Center, Petah-Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Israel; 5AiCuris Anti-infective Cures, Wuppertal, Germany; 6UCL Department of Applied Health Research, University College London, London, UK; 7Informatics Unit, Fundació Institut Català de Farmacologia, Barcelona, Spain; 8Department of Medical Microbiology, Southmead Hospital, North Bristol NHS Trust, Bristol, UK; 9Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands Purpose: Complicated urinary tract infections (cUTIs) are among the most frequent health-care-associated infections. In patients with cUTI, Pseudomonas aeruginosa deserves special attention, since it can affect patients with serious underlying conditions. Our aim was to gain insight into the risk factors and prognosis of P. aeruginosa cUTIs in a scenario of increasing multidrug resistance (MDR). Methods: This was a multinational, retrospective, observational study at 20 hospitals in south and southeastern Europe, Turkey, and Israel including consecutive patients with cUTI hospitalized between January 2013 and December 2014. A mixed-effect logistic regression model was performed to assess risk factors for P. aeruginosa and MDR P. aeruginosa cUTI.Results: Of 1,007 episodes of cUTI, 97 (9.6%) were due to P. aeruginosa. Resistance rates of P. aeruginosa were: antipseudomonal cephalosporins 35 of 97 (36.1%), aminoglycosides 30 of 97 (30.9%), piperacillin–tazobactam 21 of 97 (21.6%), fluoroquinolones 43 of 97 (44.3%), and carbapenems 28 of 97 (28.8%). The MDR rate was 28 of 97 (28.8%). Independent risk factors for P. aeruginosa cUTI were male sex (OR 2.61, 95% CI 1.60–4.27), steroid therapy (OR 2.40, 95% CI 1.10–5.27), bedridden functional status (OR 1.79, 95% CI 0.99–3.25), antibiotic treatment within the previous 30 days (OR 2.34, 95% CI 1.38–3.94), indwelling urinary catheter (OR 2.41, 95% CI 1.43–4.08), and procedures that anatomically modified the urinary tract (OR 2.01, 95% CI 1.04–3.87). Independent risk factors for MDR P. aeruginosa cUTI were age (OR 0.96, 95% CI 0.93–0.99) and anatomical urinary tract modification (OR 4.75, 95% CI 1.06–21.26). Readmission was higher in P. aeruginosa cUTI patients than in other etiologies (23 of 97 [23.7%] vs 144 of 910 [15.8%], P=0.04), while 30-day mortality was not significantly different (seven of 97 [7.2%] vs 77 of 910 [8.5%], P=0.6).Conclusion: Patients with P. aeruginosa cUTI had characteristically a serious baseline condition and manipulation of the urinary tract, although their mortality was not higher than that of patients with cUTI caused by other etiologies. Keywords: health care-associated infections, complicated urinary tract infections, Pseudomonas aeruginosa, multidrug-resistanc
Vibrational wavepacket dynamics in Fe carbene photosensitizer determined with femtosecond X-ray emission and scattering
The non-equilibrium dynamics of electrons and nuclei govern the function of photoactive materials. Disentangling these dynamics remains a critical goal for understanding photoactive materials. Here we investigate the photoinduced dynamics of the [Fe(bmip)2]2+ photosensitizer, where bmipâ=â2,6-bis(3-methyl-imidazole-1-ylidine)-pyridine, with simultaneous femtosecond-resolution Fe Kα and KÎČ X-ray emission spectroscopy (XES) and X-ray solution scattering (XSS). This measurement shows temporal oscillations in the XES and XSS difference signals with the same 278âfs period oscillation. These oscillations originate from an Fe-ligand stretching vibrational wavepacket on a triplet metal-centered (3MC) excited state surface. This 3MC state is populated with a 110âfs time constant by 40% of the excited molecules while the rest relax to a 3MLCT excited state. The sensitivity of the Kα XES to molecular structure results from a 0.7% average Fe-ligand bond length shift between the 1âs and 2p core-ionized states surfaces