Investigation of slowing down and charge-exchange of nickel and uranium ions in gases and solids in the energy range (60 - 200) MeV/u

In this thesis new slowing down and charge-state measurements will be presented in the energy range of (60 - 200) MeV/u. These measurements were done using the Fragment Separator (FRS) facility at GSI in Darmstadt. The presented data were taken during two experimental runs. The experiments were divided into two parts. In the first part a 200 MeV/u Ni27+ beam was used. The evolution of charge states as a function of the target thickness was investigated covering both the non-equilibrium and equilibrium region. This was done with various mono-atomic materials (Z2 = 6, 7, 10, 13, 18, 22) and compound materials (ethylene, polyethylene and polypropylene). From the measured charge-state distributions the one-electron ionization and capture cross sections have been extracted. A 40 % gas-solid difference is observed in the ionization cross sections for the mono-atomic materials. In the compound materials a 30 % difference is observed between ethylene and the polymers. The experimental cross sections for the mono-atomic materials have been compared with theoretical calculations [1, 2]. The theoretical ionization cross sections agree quite well with the corresponding experimental ionization cross sections. In the gaseous targets the agreement between experiment and theory is better than 3 %. For the capture cross sections the agreement between experiment and theory is also very good for the lighter target materials (Z2 <= 7). For the heavier targets large deviations up to one order of magnitude are observed. These deviations are due to the increasing importance of the non-radiative capture channel in heavier target materials which is quite difficult to calculate accurately. The results motivate for further refinement of the theory in this energy region. In the second part 3 different uranium beams were used with initial energies of 61 MeV/u (U86+ incident), 85 MeV/u (U73+ incoming) and 200 MeV/u (U81+ incident) to measure the evolution of the charge states again and the energy loss as a function of the target thickness in the same materials as used in the first part plus some additional mono-atomic materials Z2 = 29, 36, 47, 54. From the measured charge-state distributions and energy losses the mean charges and stopping forces have been extracted. At 61 MeV/u we observe a gas-solid difference in the mean charge of up to 4 charge states for the mono-atomic materials. The corresponding stopping powers (forces) at the same specific energy only show a gas-solid difference for light materials (Z2 <= 7). The stopping forces are compared with calculations done with the PASS code [3, 4], ATIMA code [5] and the Hubert et al. tables [6]. The agreement is quite good between experiment and theory. The PASS code predicts by using the experimental mean charges a gas-solid difference in the stopping force for the heavier target materials. In the data at 200 MeV/u there is a gas-solid difference in the ionization rate for U81+ ions similar to the Ni27+ results.In dieser Dissertation werden neue Ladungsverteilungen und Energieverlustmessungen präsentiert. Diese Messungen wurden am Fragment Separator (FRS) bei der GSI in Darmstadt durchgeführt. Die Daten, die hier vorgestellt werden, wurden in zwei Experimenten aufgenommen. Die Experimente bestanden aus zwei Teilen. Im ersten Teil wurde mit einem 200 MeV/u Ni27+ Strahl gemessen. Ziel dieser Messung war die Entwicklung der Ladungsverteilung als Funktion der Targetdicke vom Nichtgleichgewicht bis Gleichgewicht zu untersuchen. Dies wurde mit verschiedenen Targets gemacht (Z2 = 6, 7, 10, 13, 18, 22, Äthylen, Polyäthylen und Polypropylen). Von den gemessenen Ladungsverteilung konnten die Umladungsquerrschnitte für Elektroneneinfang und -verlust extrahiert werden. Ein Gas-Festkörper Effekt von 40 % wurde im Ionizationsquerrschnitt für die monoatomaren (reinen Elemente) Targets gemessen. Im Äthylen und den Polymeren (Polyäthylen und Polypropylen) war ein Effekt von 30 % zu sehen. Die experimentellen Umladungsquerrschnitte für die monoatomaren Targets wurden mit theoretischen Rechnungen von A. Surzhykov und S. Fritzsche [1] und V. P. Shevelko [2] verglichen. In der Ionization stimmen die theoretischen Rechnungen mit den experimentellen Werten gut überein. In den Gastargets ist die Übereinstimmung besser als 3 %. Im Elektroneneinfang gibt es gute Übereinstimmung zwischen Experiment und Theorie bei den leichten Targets (Z2 <= 7), bei den schweren Targets gibt es grosse Abweichungen bis zu einer Grössenordnung. Diese Abweichung kommt zustande, weil der nicht-radiative Querrschnitt einen grösseren Anteil hat bei den schweren Targets und dieser Teil sehr schwer theoretisch zu rechnen ist. Die Ergebnisse sind eine Motivation für Verbesserungen in der Theorie im diesen Energiebereich. Im zweiten Teil wurde ein Uranstrahl bei drei verschiedenen Energien benutzt, diese waren 61 MeV/u mit 86+ als Eingangsladungszustand, 85 MeV/u mit 73+ als Eingangsladungszustand und 200 MeV/u mit 81+ als Eingangsladungszustand. Ziel dieser Messung war es wiederum, die Entwicklung der Ladungsverteilung zu untersuchen und auch Energieverluste zu messen. Dieselben Targets wurden benutzt und zusätzlich wurden folgende Targets vermessen Z2 = 29, 36, 47, 54. Von den gemessenen Ladungsverteilungen und Energieverlusten wurde die mittlere Ladung und das Bremsvermögen bestimmt. Bei 61 MeV/u ist ein Gas-Festkörper Effekt in der mittleren Ladung bei den monoatomaren Targets zu sehen. Der Effekt hat eine Grösse von fast 4 Ladungen. Das dazu gehörige Bremsvermögen zeigt nur einen Gas-Festkörper Effekt bei den leichteren Targets (Z2 <= 7). Die experimentellen Werte wurden mit dem PASS Programm [3, 4], dem ATIMA Programm [5] und den Hubert et al. Tabellen [6] verglichen. Die theoretischen Rechnungen von den Programmen stimmen mit den experimentellen Werten gut überein. PASS sagt einen Gas-Festkörper Effekt bei den schwereren Targets voraus, weil experimentelle Ladungen als Eingangsparameter benutzt wurden. Bei der 200 MeV/u Messung wurde ein Gas-Festkörper Unterschied in der Ionizationsrate in der Entwicklung des U81+ Ladungszustand beobachtet, ähnlich wie in der Ni27+ Messung

Bloodstream infections in community hospitals in the 21st century: A multicenter cohort study

Background: While the majority of healthcare in the US is provided in community hospitals, the epidemiology and treatment of bloodstream infections in this setting is unknown. Methods and Findings: We undertook this multicenter, retrospective cohort study to 1) describe the epidemiology of bloodstream infections (BSI) in a network of community hospitals and 2) determine risk factors for inappropriate therapy for bloodstream infections in community hospitals. 1,470 patients were identified as having a BSI in 9 community hospitals in the southeastern US from 2003 through 2006. The majority of BSIs were community-onset, healthcare associated (n = 823, 56%); 432 (29%) patients had community-acquired BSI, and 215 (15%) had hospital-onset, healthcare-associated BSI. BSIs due to multidrug-resistant pathogens occurred in 340 patients (23%). Overall, the three most common pathogens were S. aureus (n = 428, 28%), E. coli (n = 359, 24%), coagulase-negative Staphylococci (n = 148, 10%), though type of infecting orgaism varied by location of acquisition (e.g., community-acquired). Inappropriate empiric antimicrobial therapy was given to 542 (38%) patients. Proportions of inappropriate therapy varied by hospital (median = 33%, range 21-71%). Multivariate logistic regression identified the following factors independently associated with failure to receive appropriate empiric antimicrobial therapy: hospital where the patient received care (p,0.001), assistance with $3 ADLs (p = 0.005), Charlson score (p = 0.05), community-onset, healthcare-associated infection (p = 0.01), and hospital-onset, healthcareassociated infection (p = 0.02). Important interaction was observed between Charlson score and location of acquisition. Conclusions: Our large, multicenter study provides the most complete picture of BSIs in community hospitals in the US to date. The epidemiology of BSIs in community hospitals has changed: community-onset, healthcare-associated BSI is most common, S. aureus is the most common cause, and 1 of 3 patients with a SI receives inappropriate empiric antimicrobial therapy. Our data suggest that appropriateness of empiric antimicrobial therapy is an important and needed performance metric for physicians and hospital stewardship programs in community hospitals

Carbapenemase-Encoding Gene Copy Number Estimator (CCNE): a Tool for Carbapenemase Gene Copy Number Estimation

Carbapenemase production is one of the leading mechanisms of carbapenem resistance in Gram-negative bacteria. An increase in carbapenemase gene (blaCarb) copies is an important mechanism of carbapenem resistance. No currently available bioinformatics tools allow for reliable detection and reporting of carbapenemase gene copy numbers. Here, we describe the carbapenemase-encoding gene copy number estimator (CCNE), a ready-to-use bioinformatics tool that was developed to estimate blaCarb copy numbers from whole-genome sequencing data. Its performance on Klebsiella pneumoniae carbapenemase gene (blaKPC) copy number estimation was evaluated by simulation and quantitative PCR (qPCR), and the results were compared with available algorithms. CCNE has two components, CCNE-acc and CCNE-fast. CCNE-acc detects blaCarb copy number in a comprehensive and high-accuracy way, while CCNE-fast rapidly screens blaCarb copy numbers. CCNE-acc achieved the best accuracy (100%) and the lowest root mean squared error (RMSE; 0.07) in simulated noise data sets, compared to the assembly-based method (23.4% accuracy, 1.697 RMSE) and the OrthologsBased method (78.9% accuracy, 0.395 RMSE). In the qPCR validation, a high consistency was observed between the blaKPC copy number determined by qPCR and that determined with CCNE. Reverse transcription-qPCR transcriptional analysis of 40 isolates showed that blaKPC expression was positively correlated with the blaKPC copy numbers detected by CCNE (P, 0.001). An association study of 357 KPC-producing K. pneumoniae isolates and their antimicrobial susceptibility identified a significant association between the estimated blaKPC copy number and MICs of imipenem (P, 0.001) and ceftazidime-avibactam (P, 0.001). Overall, CCNE is a useful genomic tool for the analysis of antimicrobial resistance genes copy number; it is available at https://github.com/biojiang/ccne

Positive follow-up blood cultures identify high mortality risk among patients with Gram-negative bacteraemia

Objectives: The role of follow-up blood cultures (FUBCs) in the management of Gram-negative bacteraemia (GNB) is poorly understood. We aimed to determine the utility of FUBCs in identifying patients with increased mortality risk. Methods: An observational study with a prospectively enrolled cohort of adult inpatients with GNB was conducted at Duke University Health System from 2002 to 2015. FUBCs were defined as blood cultures performed from 24 hours to 7 days from initial positive blood culture. Results: Among 1702 patients with GNB, 1164 (68%) had FUBCs performed. When performed, FUBCs were positive in 20% (228/1113) of cases. FUBC acquisition was associated with lower all-cause in-hospital mortality (108/538, 20%, vs. 176/1164, 15%; p 0.01) and attributable in-hospital mortality (78/538, 15%, vs. 98/1164, 8%; p < 0.0001). Propensity score–weighted Cox proportional hazards models revealed that obtaining FUBCs was associated with reductions in all-cause (hazard ratio (HR) 0.629; 95% confidence interval (CI), 0.511–0.772; p < 0.0001) and attributable mortality (HR 0.628; 95% CI, 0.480–0.820; p 0.0007). Positive FUBCs were associated with increased all-cause mortality (49/228, 21%, vs. 110/885, 11%; p 0.0005) and attributable mortality (27/228, 12%, vs. 61/885, 7%; p 0.01) relative to negative FUBCs. Propensity score–weighted Cox proportional hazards models revealed that positive FUBCs were associated with increased all-cause (HR 2.099; 95% CI, 1.567–2.811; p < 0.0001) and attributable mortality (HR 1.800; 95% CI, 1.245–2.603; p 0.002). In a calibration analysis, a scoring system accurately identified patients at high risk of positive FUBCs. Conclusions: Rates of positive FUBCs were high and identified patients at increased risk for mortality. Clinical variables can identify patients at high risk for positive FUBCs. FUBCs should be considered in the management of GNB

Influence of Vancomycin Minimum Inhibitory Concentration on the Outcome of Methicillin-Susceptible Staphylococcus aureus Left-Sided Infective Endocarditis Treated with Anti-staphylococcal Beta-Lactam Antibiotics; a Prospective Cohort Study by the International Collaboration on Endocarditis

Objectives: Left-sided methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis treated with cloxacillin has a poorer prognosis when the vancomycin minimum inhibitory concentration (MIC) is ≥1.5 mg/L. We aimed to validate this using the International Collaboration on Endocarditis cohort and to analyse whether specific genetic characteristics were associated with a high vancomycin MIC (≥1.5 mg/L) phenotype. Methods: All patients with left-sided MSSA infective endocarditis treated with antistaphylococcal β-lactam antibiotics between 2000 and 2006 with available isolates were included. Vancomycin MIC was determined by Etest as either high (≥1.5 mg/L) or low (<1.5 mg/L). Isolates underwent spa typing to infer clonal complexes and multiplex PCR for identifying virulence genes. Univariate analysis was performed to evaluate the association between in-hospital and 1-year mortality, and vancomycin MIC phenotype. Results: Sixty-two cases met the inclusion criteria. Vancomycin MIC was low in 28 cases (45%) and high in 34 cases (55%). No significant differences in patient demographic data or characteristics of infection were observed between patients with infective endocarditis due to high and low vancomycin MIC isolates. Isolates with high and low vancomycin MIC had similar distributions of virulence genes and clonal lineages. In-hospital and 1-year mortality did not differ significantly between the two groups (32% (9/28) vs. 27% (9/34), p 0.780; and 43% (12/28) vs. 29% (10/34), p 0.298, for low and high vancomycin MIC respectively). Conclusions: In this international cohort of patients with left-sided MSSA endocarditis treated with antistaphylococcal β-lactams, vancomycin MIC phenotype was not associated with patient demographics, clinical outcome or virulence gene repertoire

The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant Enterobacteriaceae

In the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), trimethoprim-sulfamethoxazole (TMP-SMX) had a limited role in the treatment of less severe carbapenem-resistant Enterobacteriaceae (CRE) infections, especially urinary tract infections. Of tested CRE, only 29% were susceptible to TMPSMX. Development of resistance further limits the use of TMPSMX in CRE infections

Transmission of Carbapenem-Resistant Klebsiella pneumoniae in US Hospitals

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated CRKp clustering in patients in US hospitals. Methods: From April 2016 to August 2017, 350 patients with clonal group 258 CRKp were enrolled in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae, a prospective, multicenter, cohort study. A maximum likelihood tree was constructed using RAxML. Static clusters shared ≤21 single-nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster. Results: Most patients were admitted from home (n = 150, 43%) or long-term care facilities (n = 115, 33%). Urine (n = 149, 43%) was the most common isolation site. Overall, 55 static and 47 dynamics clusters were identified involving 210 of 350 (60%) and 194 of 350 (55%) patients, respectively. Approximately half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intrasystem and 22 (40%) intersystem clusters. Dynamic clusters consisted of 32 (68%) intrasystem and 15 (32%) intersystem clusters and had fewer SNP differences than static clusters (8 vs 9; P =. 045; 95% confidence interval [CI]: -4 to 0). Dynamic intersystem clusters contained more patients than dynamic intrasystem clusters (median [interquartile range], 4 [2, 7] vs 2 [2, 2]; P =. 007; 95% CI: -3 to 0). Conclusions: Widespread intrasystem and intersystem transmission of CRKp was identified in hospitalized US patients. Use of different methods for assessing genetic similarity resulted in only minor differences in interpretation

Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agarbased antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae

Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study

Background: Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA. Methods: CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227. Findings: 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45–71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20–28) of these patients had died. Interpretation: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales. Funding: National Institutes of Health

Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries. Methods: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete. Findings: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2–6] vs 2 [0–4] vs 2 [0–4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2–5] vs 1 [0–3] vs 1 [0–2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42–65) for China versus South America, 50% (41–61) for the USA versus China, and 53% (41–66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8–16; 29 of 246) than in the USA (23%, 16–30; 30 of 130) and South America (28%, 20–37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22–10·50) and the USA (aOR 3·34, 1·50–7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70–2·96). Interpretation: Global CRKP epidemics have important regional differences in patients’ baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions. Funding: The National Institutes of Health