Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.

Mechanisms of the Removal of U(VI) from Aqueous Solution Using Biochar: A Combined Spectroscopic and Modeling Approach.

Biochar has been touted as a promising sorbent for the removal of inorganic contaminants, such as uranium (U), from water. However, the molecular-scale mechanisms of aqueous U(VI) species adsorption to biochar remain poorly understood. In this study, two approaches, grounded in equilibrium thermodynamics, were employed to investigate the U(VI) adsorption mechanisms: (1) batch U(VI) adsorption experiments coupled to surface complexation modeling (SCM) and (2) isothermal titration calorimetry (ITC), supported by synchrotron-based X-ray absorption spectroscopy (XAS) analyses. The biochars tested have considerable proton buffering capacity and most strongly adsorb U(VI) between approximately pH 4 and 6. FT-IR and XPS studies, along with XAS analyses, show that U(VI) adsorption occurs primarily at the proton-active carboxyl (-COOH) and phenolic hydroxyl (-OH) functional groups on the biochar surface. The SCM approach is able to predict U(VI) adsorption behavior across a wide range of pH and at varying initial U(VI) and biochar concentrations, and U adsorption is strongly influenced by aqueous U(VI) speciation. Supporting ITC measurements indicate that the calculated enthalpies of protonation reactions of the studied biochar, as well as the adsorption of U(VI), are consistent with anionic oxygen ligands and are indicative of both inner- and outer-sphere complexation. Our results provide new insights into the modes of U(VI) adsorption by biochar and more generally improve our understanding of its potential to remove radionuclides from contaminated waters.

Osteopathic Manipulative Treatment for the Management of Adjacent Segment Pathology.

Adjacent segment pathology is an adverse effect of spinal fusion that precipitates accelerated spinal degenerative changes at vertebral segments contiguous with the fused vertebrae. The accelerated degeneration related to ASP can be challenging to manage, as it can lead to conditions such as radiculopathy and can create the need for reoperation. In the present case, a 50-year-old woman with a previous spinal fusion presented with a 1-year history of progressive low back pain, lumbar radiculopathy, and sciatica. Osteopathic manipulative treatment was used to manage her pain, and the patient reported that the treatment provided long-term resolution of her sciatica symptoms. This case demonstrates an effective use of osteopathic manipulative treatment in the conservative management of lumbar radiculopathy related to adjacent segment pathology.

Effect of a Mandatory Third-Year Osteopathic Manipulative Treatment Course on Student Attitudes.

CONTEXT: Despite interest by osteopathic medical students in learning and incorporating osteopathic manipulative treatment (OMT) techniques into their future practices, most students indicate that OMT is rarely or never taught during many clinical rotations. OBJECTIVE: To determine whether a mandatory OMT course taken during the third year of medical school would influence students' exposure to OMT, confidence in OMT, intent to continue developing OMT skills, and plan to provide OMT as practicing physicians. METHODS: A mandatory pilot OMT course was implemented in the 2014 third-year curriculum. A survey was then developed to assess students' attitudes toward OMT. Surveys were administered to students whose third year was in 2013 and thus had not taken the course (group 1) and to students who had taken the course in 2014 (group 2). RESULTS: Of the 223 students in group 1, 143 (64%) responded. Of the 213 students in group 2, 112 (53%) responded. Students in group 2 reported greater exposure to OMT compared with students in group 1, higher confidence levels in practicing OMT (61 [54%] vs 71 [50%]), greater intent to continue developing OMT skills, and plan to provide OMT as practicing physicians (91 [81%] vs 94 [66%]). CONCLUSION: A pilot course in OMT increased students' levels of confidence in and intent to provide OMT in their future practices.

Predictive relationship of osteopathic manual medicine grades and COMLEX-USA Level 1 total scores and osteopathic principles and practice subscores.

CONTEXT: Osteopathic manual medicine (OMM) encompasses hands-on diagnosis and treatment as part of patient care. The area of osteopathic principles and practice (OPP) is considered a core competency for students and practitioners of this medical tradition. The Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) is a useful tool for assessing candidates' competency. OBJECTIVES: To examine the relationship of COMLEX-USA Level 1 total scores and OPP subscores with OMM course grades, and to determine if these grades are predictive of COMLEX-USA Level 1 OPP performance. METHODS: The authors collected data-COMLEX-USA Level 1 total and OPP subscores, OMM grades (written, practical, and total for first and second academic years), sex, and age-for a cohort of osteopathic medical students at a single institution, and these data were then analyzed by means of correlation analysis. RESULTS: Records were obtained from a second-year class of osteopathic medical students (N=217). The authors' analysis of total scores and OPP subscores on COMLEX-USA Level 1 yielded a statistically significant correlation with all variables. Although the correlations were moderate, second-year written examination grades showed the strongest association with the COMLEX-USA Level 1 OPP subscores (r=0.530) and total scores (r=0.566). CONCLUSION: Performance in the second-year OMM written examination could identify students potentially at risk for poor performance on COMLEX-USA Level 1.

Submicron hard X-ray fluorescence imaging of synthetic elements.

Synchrotron-based X-ray fluorescence microscopy (XFM) using hard X-rays focused into sub-micron spots is a powerful technique for elemental quantification and mapping, as well as microspectroscopic measurements such as µ-XANES (X-ray absorption near edge structure). We have used XFM to image and simultaneously quantify the transuranic element plutonium at the L(3) or L(2)-edge as well as Th and lighter biologically essential elements in individual rat pheochromocytoma (PC12) cells after exposure to the long-lived plutonium isotope (242)Pu. Elemental maps demonstrate that plutonium localizes principally in the cytoplasm of the cells and avoids the cell nucleus, which is marked by the highest concentrations of phosphorus and zinc, under the conditions of our experiments. The minimum detection limit under typical acquisition conditions with an incident X-ray energy of 18 keV for an average 202 µm(2) cell is 1.4 fg Pu or 2.9×10(-20) moles Pu µm(-2), which is similar to the detection limit of K-edge XFM of transition metals at 10 keV. Copper electron microscopy grids were used to avoid interference from gold X-ray emissions, but traces of strontium present in naturally occurring calcium can still interfere with plutonium detection using its L(α) X-ray emission.

Adsorption of aqueous uranyl complexes onto Bacillus subtilis cells.

In oxygenated, CO2-rich systems, negatively charged uranyl complexes dominate the aqueous uranium speciation, and it is commonly assumed that these complexes exhibit negligible adsorption onto negatively charged surfaces such as bacteria. We measured the adsorption of 4.2 x 10(-6) M aqueous uranium onto Bacillus subtilis from pH 1.5 to 9 and with wet weight bacterial concentrations from 0.125 to 0.5 g/L. Experiments were performed in the presence and absence of dissolved CO2, and additional experiments were performed in the presence of dissolved CO2 and Ca. We observed extensive uranium adsorption onto the bacterial surface under all conditions. Thermodynamic modeling of the data suggests that uranylhydroxide, uranyl-carbonate, and calcium-uranylcarbonate species each can form stable surface complexes on the bacterial cell wall. These results could dramatically alter predictions of uranium mobility in near-surface environments.