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Rationale: Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) pulmonary disease (PD), which exhibits increasing global incidence. Current microbiologic methods routinely used in clinical practice lack sensitivity and have long latencies, leading to delays in diagnosis and treatment initiation and evaluation. A clustered regularly interspaced short palindromic repeats (CRISPR)-based assay that measures MAC cell-free DNA (cfDNA) concentrations in serum could provide a rapid means to detect MAC infection and monitor response to antimicrobial treatment. Objectives: To develop and optimize a CRISPR MAC assay for MAC infection detection and to evaluate its diagnostic and prognostic performance in two MAC disease cohorts. Methods: MAC cfDNA serum concentrations were measured in individuals with diagnoses of MAC disease or who had bronchiectasis or chronic obstructive pulmonary disease diagnoses without histories of NTM PD or NTM-positive sputum cultures. Diagnostic performance was analyzed using pretreatment serum from two cohorts. Serum MAC cfDNA changes during MAC PD treatment were evaluated in a subset of patients with MAC PD who received macrolide-based multidrug regimens. Measurements and Main Results: The CRISPR MAC assay detected MAC cfDNA in MAC PD with 97.6% (91.6-99.7%) sensitivity and 97.6% (91.5-99.7%) specificity overall. Serum MAC cfDNA concentrations markedly decreased after MAC-directed treatment initiation in patients with MAC PD who demonstrated MAC culture conversion. Conclusions: This study provides preliminary evidence for the utility of a serum-based CRISPR MAC assay to rapidly detect MAC infection and monitor the response to treatment.

Purpose To evaluate the impact of an artificial intelligence (AI) assistant for lung cancer screening on multinational clinical workflows. Materials and Methods An AI assistant for lung cancer screening was evaluated on two retrospective randomized multireader multicase studies where 627 (141 cancer-positive cases) low-dose chest CT cases were each read twice (with and without AI assistance) by experienced thoracic radiologists (six U.S.-based or six Japan-based radiologists), resulting in a total of 7524 interpretations. Positive cases were defined as those within 2 years before a pathology-confirmed lung cancer diagnosis. Negative cases were defined as those without any subsequent cancer diagnosis for at least 2 years and were enriched for a spectrum of diverse nodules. The studies measured the readers' level of suspicion (on a 0-100 scale), country-specific screening system scoring categories, and management recommendations. Evaluation metrics included the area under the receiver operating characteristic curve (AUC) for level of suspicion and sensitivity and specificity of recall recommendations. Results With AI assistance, the radiologists' AUC increased by 0.023 (0.70 to 0.72; P = .02) for the U.S. study and by 0.023 (0.93 to 0.96; P = .18) for the Japan study. Scoring system specificity for actionable findings increased 5.5% (57% to 63%; P < .001) for the U.S. study and 6.7% (23% to 30%; P < .001) for the Japan study. There was no evidence of a difference in corresponding sensitivity between unassisted and AI-assisted reads for the U.S. (67.3% to 67.5%; P = .88) and Japan (98% to 100%; P > .99) studies. Corresponding stand-alone AI AUC system performance was 0.75 (95% CI: 0.70, 0.81) and 0.88 (95% CI: 0.78, 0.97) for the U.S.- and Japan-based datasets, respectively. Conclusion The concurrent AI interface improved lung cancer screening specificity in both U.S.- and Japan-based reader studies, meriting further study in additional international screening environments. Keywords: Assistive Artificial Intelligence, Lung Cancer Screening, CT Supplemental material is available for this article. Published under a CC BY 4.0 license.

Background: Antimicrobials cause perturbations in the composition and diversity of the host microbiome. We aimed to compare gut microbiome perturbations caused by oral tebipenem pivoxil hydrobromide (a novel carbapenem) and by amoxicillin-clavulanic acid (an orally administered β-lactam-β-lactam inhibitor combination widely used in clinical practice)., Methods: We did a phase 1, single-centre, randomised, parallel-group, active-control trial to evaluate the effect of tebipenem pivoxil hydrobromide on the human gut microbiota. Healthy participants aged 18 years or older with no documented illnesses during recruitment were enrolled at Karolinska University Hospital (Stockholm, Sweden). Study participants were stratified by sex and block-randomised in a 1:1 ratio to treatment with either tebipenem pivoxil hydrobromide (600 mg orally every 8 h) or amoxicillin-clavulanic acid (500 mg amoxicillin and 125 mg clavulanic acid orally every 8 h). The study included 10 days of treatment (days 1-10) and four follow-up visits (days 14, 21, 90, and 180). The trial was open-label for clinical investigators and patients, but masked for microbiology investigators. Faecal samples were collected at all visits. Sequencing of 16S rDNA was used to measure the diversity metrics, and quantitative culture to quantify selected taxa. The primary outcomes were changes in the α and β diversity and log count of colony-forming units for selected taxa between samples compared with baseline (day 1), and whether any changes reverted during the follow-up period. The analyses were done in the intention-to-treat population. This study was registered with ClinicalTrials.gov (NCT04376554)., Findings: The study was conducted between Jan 23, 2020, and April 6, 2021. 49 volunteers were screened for eligibility, among whom 30 evaluable participants (14 men and 16 women) were assigned: 15 (50%) to the tebipenem pivoxil hydrobromide group and 15 (50%) to the amoxicillin-clavulanic acid group. Baseline characteristics were similar between groups. Complete follow-up was available for all participants, and all participants except one completed treatment as assigned. The diversity metrics showed significant changes from baseline during the treatment period. Significant decreases in richness were observed on days 4-10 (p≤0·0011) in the amoxicillin-clavulanic acid group and on days 4-14 (p≤0·0019) in the tebipenem pivoxil hydrobromide group. Similarly, evenness was significantly decreased during treatment in the amoxicillin-clavulanic acid group (day 4, p=0·030) and the tebipenem pivoxil hydrobromide group (days 4-10, p<0·0001) compared with baseline. Quantitative cultures showed significant decreases in Enterobacterales (days 4-7, p≤0·0030), Enterococcus spp (days 4-14, p=0·025 to p<0·0001), Bifidobacterium spp (days 2-4, p≤0·026), and Bacteroides spp (days 4-10, p≤0·030) in the tebipenem pivoxil hydrobromide group. Similarly, in amoxicillin-clavulanic acid recipients, significant changes were observed in Enterobacterales (days 4-10, p≤0·048), Bifidobacterium spp (days 2-4, p≤0·013), and Lactobacillus spp (days 2-4, p≤0·020). Samples from the follow-up period were not significantly different from those at baseline in β diversity analysis (PERMANOVA, p>0·99). By the end of the study, no significant change was observed compared with baseline in either group. There were no deaths or severe adverse events., Interpretation: The impact of tebipenem pivoxil hydrobromide on the gut microbiome was similar to that of amoxicillin-clavulanic acid. The safety of antibiotic use with regard to the microbiome should be given attention, as dysbiosis is associated with health and disease., Funding: Spero Therapeutics., Competing Interests: Declaration of interests MN, DM, PBE, and IAC were employees of Spero Therapeutics and LBG was a consultant at Spero Therapeutics during the study. No personal honoraria were paid out to any of the academic investigators. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Over million years, convergence between the Nazca and South America tectonic plates results in Andean orogeny. Over decades/centuries, it fuels the earthquake cycle of the Andean megathrust. It is well recognised that, over the geologically-long term of million years, Andean orogeny feeds back onto plate convergence rates, generating temporal changes documented throughout the Neogene. In contrast, no feedback mechanism operated over the geologically-short term by the earthquake cycle is currently contemplated. In fact, it is commonly assumed that the rates of contemporary convergence, which are accurately measured via geodesy, remain steady during the megathrust earthquake cycle. Here we investigate whether the contemporary Nazca/South America plate motion varies over year-/decade-long periods in response to megathrust stress variations associated with the earthquake cycle. We focus on the decade preceding the three largest and most recent [Formula: see text] earthquakes (2010 [Formula: see text] Maule, 2014 [Formula: see text] Iquique, 2015 [Formula: see text] Illapel), and find slowdowns of both Nazca and South America whole-plate motions that exceed the impact of data uncertainty or noise. We show that the torque variations required upon Nazca and South America to generate the slowdowns are consistent with that arising from the buildup of interseismic stress preceding the earthquakes., (© 2023. The Author(s).)

The clinical relevance of bacteriuria following antibiotic treatment of complicated urinary tract infections in clinical trials remains controversial. We evaluated the impact of urine pharmacokinetics on the timing of recurrent bacteriuria in a recently completed trial that compared oral tebipenem pivoxil hydrobromide to intravenous ertapenem. The urinary clearance and urine dwell time of ertapenem were prolonged relative to tebipenem and were associated with a temporal difference in the repopulation of bladder urine with bacteria following treatment, potentially confounding the assessment of efficacy., Competing Interests: D.M., A.K.T., V.K.G., I.A.C., P.B.E., K.A.H., and N.B. were employees or consultants of and may have held stock in Spero Therapeutics, Inc. V.K.G. is currently an employee of Arcus Biosciences, Hayward, C.A. D.A. is an employee of GlaxoSmithKline. G.M. is the owner of Moore Consulting and has received consulting fees from Spero Therapeutics, Inc. C.M.R., S.M.B., and P.G.A. are employees of Institute for Clinical Pharmacodynamics, Inc., and have received research support from Spero Therapeutics, Inc.

Importance: Multimodal generative artificial intelligence (AI) methodologies have the potential to optimize emergency department care by producing draft radiology reports from input images., Objective: To evaluate the accuracy and quality of AI-generated chest radiograph interpretations in the emergency department setting., Design, Setting, and Participants: This was a retrospective diagnostic study of 500 randomly sampled emergency department encounters at a tertiary care institution including chest radiographs interpreted by both a teleradiology service and on-site attending radiologist from January 2022 to January 2023. An AI interpretation was generated for each radiograph. The 3 radiograph interpretations were each rated in duplicate by 6 emergency department physicians using a 5-point Likert scale., Main Outcomes and Measures: The primary outcome was any difference in Likert scores between radiologist, AI, and teleradiology reports, using a cumulative link mixed model. Secondary analyses compared the probability of each report type containing no clinically significant discrepancy with further stratification by finding presence, using a logistic mixed-effects model. Physician comments on discrepancies were recorded., Results: A total of 500 ED studies were included from 500 unique patients with a mean (SD) age of 53.3 (21.6) years; 282 patients (56.4%) were female. There was a significant association of report type with ratings, with post hoc tests revealing significantly greater scores for AI (mean [SE] score, 3.22 [0.34]; P < .001) and radiologist (mean [SE] score, 3.34 [0.34]; P < .001) reports compared with teleradiology (mean [SE] score, 2.74 [0.34]) reports. AI and radiologist reports were not significantly different. On secondary analysis, there was no difference in the probability of no clinically significant discrepancy between the 3 report types. Further stratification of reports by presence of cardiomegaly, pulmonary edema, pleural effusion, infiltrate, pneumothorax, and support devices also yielded no difference in the probability of containing no clinically significant discrepancy between the report types., Conclusions and Relevance: In a representative sample of emergency department chest radiographs, results suggest that the generative AI model produced reports of similar clinical accuracy and textual quality to radiologist reports while providing higher textual quality than teleradiologist reports. Implementation of the model in the clinical workflow could enable timely alerts to life-threatening pathology while aiding imaging interpretation and documentation.

Excessive opioid prescribing following surgery creates a reservoir of unused medications available for diversion and abuse. We conducted a cohort study examining the impact of clinic-based, surgeon-initiated strategies using an activated charcoal bag (ACB) system on disposal of unused opioids. Among patients undergoing a variety of general surgery procedures, 67% of those with unused opioids disposed of them using the ACB. Our findings demonstrate practical ways to incorporate opioid disposal into surgical practice as a complement to judicious opioid prescribing., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CL R ) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem., Competing Interests: The authors declare a conflict of interest. M.C.S., S.M.B., and C.M.R. are employees of the Institute for Clinical Pharmacodynamics, Inc., which has received research support from Spero Therapeutics, Inc. H.G. was an employee of ICPD at the time the analyses were conducted and is currently and employee of Certara USA. V.K.G., A.K.T., and D.M. were employees of Spero Therapeutics, Inc. at the time the analyses were conducted. D.M. is currently an employee of D&J Consulting and V.K.G is currently an employee of Arcus Biosciences.

Objective: In order to effectively create and implement an educational program to improve opioid prescribing practices, it is important to first consider the unique perspectives of residents on the frontlines of the opioid epidemic. We sought to better understand resident perspectives on opioid prescribing, current practices in pain management, and opioid education as a needs assessment for designing future educational interventions., Design: This is a qualitative study using focus groups of surgical residents at 4 different institutions., Setting: We conducted focus groups using a semistructured interview guide in person or over video conferencing. The residency programs selected for participation represent a broad geographic range and varying residency sizes., Participants: We used purposeful sampling to recruit general surgery residents from the University of Utah, University of Wisconsin, Dartmouth-Hitchcock Medical Center, and the University of Alabama at Birmingham. All general surgery residents at these locations were eligible for inclusion. Participants were assigned to focus groups by residency site and their status as junior (PGY-2, PGY-3) or senior resident (PGY-4, PGY-5)., Results: We completed 8 focus groups with a total of 35 residents included. We identified 4 main themes. First, residents relied on clinical and nonclinical factors when making decisions about opioid prescribing. However, hidden curricula based on unique institutional cultures and attending preferences heavily influenced residents' prescribing practices. Second, residents acknowledged that stigma and biases towards certain patient groups influenced opioid prescribing practices. Third, residents encountered barriers within their health systems to evidence-based opioid prescribing. Fourth, residents did not routinely receive formal education on pain management or opioid prescribing. Residents recommended several interventions to improve the current state of opioid prescribing, including standardized prescribing guidelines, improved patient education, and formal training during the first year of residency., Conclusions: Our study highlighted several areas of opioid prescribing that can be improved upon through educational interventions. These findings can be used to develop programs aimed at improving residents' opioid prescribing practices, both during and after training, and ultimately the safe care of surgical patients., Ethics Statement: This project was approved by the University of Utah Institutional Review Board, ID # 00118491. All participants provided written informed consent., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background Developing deep learning models for radiology requires large data sets and substantial computational resources. Data set size limitations can be further exacerbated by distribution shifts, such as rapid changes in patient populations and standard of care during the COVID-19 pandemic. A common partial mitigation is transfer learning by pretraining a "generic network" on a large nonmedical data set and then fine-tuning on a task-specific radiology data set. Purpose To reduce data set size requirements for chest radiography deep learning models by using an advanced machine learning approach (supervised contrastive [SupCon] learning) to generate chest radiography networks. Materials and Methods SupCon helped generate chest radiography networks from 821 544 chest radiographs from India and the United States. The chest radiography networks were used as a starting point for further machine learning model development for 10 prediction tasks (eg, airspace opacity, fracture, tuberculosis, and COVID-19 outcomes) by using five data sets comprising 684 955 chest radiographs from India, the United States, and China. Three model development setups were tested (linear classifier, nonlinear classifier, and fine-tuning the full network) with different data set sizes from eight to 8 5 . Results Across a majority of tasks, compared with transfer learning from a nonmedical data set, SupCon reduced label requirements up to 688-fold and improved the area under the receiver operating characteristic curve (AUC) at matching data set sizes. At the extreme low-data regimen, training small nonlinear models by using only 45 chest radiographs yielded an AUC of 0.95 (noninferior to radiologist performance) in classifying microbiology-confirmed tuberculosis in external validation. At a more moderate data regimen, training small nonlinear models by using only 528 chest radiographs yielded an AUC of 0.75 in predicting severe COVID-19 outcomes. Conclusion Supervised contrastive learning enabled performance comparable to state-of-the-art deep learning models in multiple clinical tasks by using as few as 45 images and is a promising method for predictive modeling with use of small data sets and for predicting outcomes in shifting patient populations. © RSNA, 2022 Online supplemental material is available for this article.

The first step towards assessing hazards in seismically active regions involves mapping capable faults and estimating their recurrence times. While the mapping of active faults is commonly based on distinct geologic and geomorphic features evident at the surface, mapping blind seismogenic faults is complicated by the absence of on-fault diagnostic features. Here we investigated the Pichilemu Fault in coastal Chile, unknown until it generated a Mw 7.0 earthquake in 2010. The lack of evident surface faulting suggests activity along a partly-hidden blind fault. We used off-fault deformed marine terraces to estimate a fault-slip rate of 0.52 ± 0.04 m/ka, which, when integrated with satellite geodesy suggests a 2.12 ± 0.2 ka recurrence time for Mw~7.0 normal-faulting earthquakes. We propose that extension in the Pichilemu region is associated with stress changes during megathrust earthquakes and accommodated by sporadic slip during upper-plate earthquakes, which has implications for assessing the seismic potential of cryptic faults along convergent margins and elsewhere., (© 2022. The Author(s).)

Background: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains., Methods: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%., Results: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache., Conclusions: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.)., (Copyright © 2022 Massachusetts Medical Society.)

SPR720 (phosphate prodrug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for nontuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow-fiber infection models. This phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers ( n  = 8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 to 2,000 mg or repeat total daily doses ranging from 500 to 1,500 mg for 7 or 14 days. SPR720 was well tolerated at daily doses of up to 1,000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting, and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious AEs were reported. The median SPR719 T max ranged from 2.8 to 8.0 h across cohorts, and the t 1/2 ranged from 2.9 to 4.5 h and was shown to be dose independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was comparable between days 7 and 14. The results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720. (This study has been registered at ClinicalTrials.gov under registration no. NCT03796910.).

Carbapenem-resistant Acinetobacter baumannii and Enterobacterales are identified as urgent threats, and multidrug-resistant (MDR) Pseudomonas aeruginosa and extended-spectrum beta-lactamase (ESBL)-producing pathogens are identified as serious threats by the Centers for Disease Control and Prevention (CDC). SPR206 is a novel polymyxin derivative with potent in vitro and in vivo activity against A. baumannii, P. aeruginosa, and multiple clinically important species of Enterobacterales , including multidrug- and extensively drug-resistant strains. This was a first-in-human (FIH) double-blind, placebo-controlled, single-, and multiple-ascending-dose study of the safety, tolerability, and pharmacokinetics (PK) of SPR206 in 94 healthy subjects. Following intravenous (i.v.) administration (1-h infusion) at single doses of 10 mg to 400 mg and multiple doses of 25 mg to 150 mg every 8 h (q8h) for 7 days and 100 mg q8h for 14 days, SPR206 was generally safe and generally well tolerated. While the incidence of adverse events increased with dose, most were of mild severity. Systemic exposure (maximum concentration of drug in serum [ C max ] and area under the concentration-time curve [AUC]) to SPR206 was approximately dose proportional, time to peak concentrations ranged from 1.1 to 1.3 h, and half-life ranged from 2.4 to 4.1 h. No appreciable accumulation occurred with repeated dosing of SPR206, and trough concentrations suggest that steady state was achieved by day 2. Urinary excretion of unchanged SPR206 was dose dependent across single- (SAD) and multiple-ascending-dose (MAD) cohorts, and the percentage of dose excreted as SPR206 was up to >50%. Importantly, no evidence of nephrotoxicity was observed over 14 days of 100 mg q8h dosing of SPR206; a dosing regimen anticipated to exceed requirements for clinical efficacy. (This study has been registered at ClinicalTrials.gov under identifier NCT03792308.).

Chest radiography (CXR) is the most widely-used thoracic clinical imaging modality and is crucial for guiding the management of cardiothoracic conditions. The detection of specific CXR findings has been the main focus of several artificial intelligence (AI) systems. However, the wide range of possible CXR abnormalities makes it impractical to detect every possible condition by building multiple separate systems, each of which detects one or more pre-specified conditions. In this work, we developed and evaluated an AI system to classify CXRs as normal or abnormal. For training and tuning the system, we used a de-identified dataset of 248,445 patients from a multi-city hospital network in India. To assess generalizability, we evaluated our system using 6 international datasets from India, China, and the United States. Of these datasets, 4 focused on diseases that the AI was not trained to detect: 2 datasets with tuberculosis and 2 datasets with coronavirus disease 2019. Our results suggest that the AI system trained using a large dataset containing a diverse array of CXR abnormalities generalizes to new patient populations and unseen diseases. In a simulated workflow where the AI system prioritized abnormal cases, the turnaround time for abnormal cases reduced by 7-28%. These results represent an important step towards evaluating whether AI can be safely used to flag cases in a general setting where previously unseen abnormalities exist. Lastly, to facilitate the continued development of AI models for CXR, we release our collected labels for the publicly available dataset., (© 2021. The Author(s).)

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an orally available prodrug of tebipenem (TBP), a carbapenem with in vitro activity against multidrug-resistant Gram-negative pathogens. This study evaluated the effects of single therapeutic and supratherapeutic doses of TBP-PI-HBr on the heart rate-corrected QT interval (QTc) by assessing the concentration-QT interval relationship using exposure-response modeling. This was a randomized, double-blind, placebo- and active-controlled, single-dose, four-way crossover study. Subjects received single oral doses of TBP-PI-HBr at 600 and 1,200 mg, placebo, and positive control (moxifloxacin at 400 mg). Cardiodynamic electrocardiograms (ECGs) and blood samples were collected in each period. Twenty-four subjects were enrolled. TBP-PI-HBr had no clinically significant adverse effects on heart rate or ECG parameters. The model-predicted slope suggests that the baseline-corrected difference in heart rate from placebo was not importantly affected by plasma TBP concentrations, supporting the use of the QT interval corrected by Fridericia's method as an appropriate correction. The model-predicted difference in QTc at the mean maximum concentration ( C max ) for TBP had negative predicted values for each dose, and no QTc prolongation was detected following TBP-PI-HBr at 600 mg or 1,200 mg. Assay sensitivity was established with moxifloxacin at 400 mg. Exposure to TBP increased in a dose-dependent manner with 600- and 1,200-mg doses. The TBP area under the concentration-time curve from time zero to infinity and C max with the 1,200-mg dose were 1.8- and 1.3-fold greater, respectively, than those with the 600-mg dose. TBP-PI-HBr was generally safe and well tolerated, with no effect in QT interval prolongation.

In active tectonic settings dominated by strike-slip kinematics, slip partitioning across subparallel faults is a common feature; therefore, assessing the degree of partitioning and strain localization is paramount for seismic hazard assessments. Here, we estimate a slip rate of 18.8 ± 2.0 mm/year over the past 9.0 ± 0.1 ka for a single strand of the Liquiñe-Ofqui Fault System, which straddles the Main Cordillera in Southern Chile. This Holocene rate accounts for ~ 82% of the trench-parallel component of oblique plate convergence and is similar to million-year estimates integrated over the entire fault system. Our results imply that strain localizes on a single fault at millennial time scale but over longer time scales strain localization is not sustained. The fast millennial slip rate in the absence of historical Mw > 6.5 earthquakes along the Liquiñe-Ofqui Fault System implies either a component of aseismic slip or Mw ~ 7 earthquakes involving multi-trace ruptures and > 150-year repeat times. Our results have implications for the understanding of strike-slip fault system dynamics within volcanic arcs and seismic hazard assessments.

In seismically-active regions, mapping active and potentially-active faults is the first step to assess seismic hazards and site selection for paleoseismic studies that will estimate recurrence rates. Here, we present a comprehensive database of active and potentially-active continental faults in Chile based on existing studies and new mapping at 1:25,000 scale using geologic and geomorphic criteria and digital elevation models derived from TanDEM-X and LiDAR data. The database includes 958 fault strands grouped into 17 fault systems and classified based on activity (81 proved, 589 probable, 288 possible). The database is a contribution to the world compilation of active faults with applications among others in seismic hazard assessments, territorial planning, paleoseismology, geodynamics, landscape evolution processes, geothermal exploration, and in the study of feedbacks between continental deformation and the plate-boundary seismic cycle along subduction zones.

Screening mammography aims to identify breast cancer at earlier stages of the disease, when treatment can be more successful 1 . Despite the existence of screening programmes worldwide, the interpretation of mammograms is affected by high rates of false positives and false negatives 2 . Here we present an artificial intelligence (AI) system that is capable of surpassing human experts in breast cancer prediction. To assess its performance in the clinical setting, we curated a large representative dataset from the UK and a large enriched dataset from the USA. We show an absolute reduction of 5.7% and 1.2% (USA and UK) in false positives and 9.4% and 2.7% in false negatives. We provide evidence of the ability of the system to generalize from the UK to the USA. In an independent study of six radiologists, the AI system outperformed all of the human readers: the area under the receiver operating characteristic curve (AUC-ROC) for the AI system was greater than the AUC-ROC for the average radiologist by an absolute margin of 11.5%. We ran a simulation in which the AI system participated in the double-reading process that is used in the UK, and found that the AI system maintained non-inferior performance and reduced the workload of the second reader by 88%. This robust assessment of the AI system paves the way for clinical trials to improve the accuracy and efficiency of breast cancer screening.

Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacteriaceae The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states. Healthy adults received single oral doses of TBPM-PI-HBr at 100 mg to 900 mg or placebo ( n  = 108) or multiple doses of 300 mg or 600 mg every 8 h or placebo ( n  = 16) for 14 days. In the single-ascending-dose (SAD) phase, mean tebipenem plasma concentrations increased in a linear and dose proportional manner for doses of 100 to 900 mg and were comparable in the fasted and fed states for the 300- and 600-mg doses. In the MAD phase, tebipenem maximum concentration ( C max ) was reached within 1.5 h and was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14. AUC was more than 2-fold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h. Approximately 55% to 60% of tebipenem was recovered in the urine. TBPM-PI-HBr was well tolerated; mild, transient diarrhea was the most commonly reported adverse event. TBPM-PI-HBr provides an orally bioavailable carbapenem option to treat serious infections caused by MDR Enterobacteriaceae and has the potential to decrease the need for intravenous antibiotic therapy in the hospital or outpatient setting. (This study has been registered at ClinicalTrials.gov under identifier NCT03395249.)., (Copyright © 2019 Eckburg et al.)

Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of tebipenem were studied in a well-characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae ( Escherichia coli , n  = 6; Klebsiella pneumoniae , n  = 5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resistance was established in a hollow-fiber infection model (HFIM). Tebipenem exhibited time-dependent pharmacodynamics that were best described by the free drug area under the concentration-time curve ( f AUC 0-24 )/MIC corrected for the length of the dosing interval ( f AUC 0-24 /MIC · 1/tau). The pharmacodynamics of tebipenem versus E. coli and K. pneumoniae were comparable, as was the response of strains possessing extended-spectrum β-lactamases versus the wild type. The median f AUC 0-24 /MIC · 1/tau value for the achievement of stasis in the 11 strains was 23. Progressively more fractionated regimens in the HFIM resulted in the suppression of resistance. An f AUC 0-24 /MIC · 1/tau value of 34.58 to 51.87 resulted in logarithmic killing and the suppression of resistance. These data and analyses will be used to define the regimen for a phase III study of adult patients with cUTI., (Copyright © 2019 American Society for Microbiology.)

Background: Hospital-acquired and ventilator-associated pneumonia (HAP/VAP; nosocomial pneumonia) due to Gram-negative pathogens are associated with significant morbidity and mortality; treatment options for multidrug-resistant infections are limited. The pivotal phase III REPROVE trial evaluated the efficacy of ceftazidime-avibactam (CAZ-AVI) vs meropenem in the treatment of patients with HAP/VAP. Study results for prespecified analyses per US Food and Drug Administration-recommended trial end points are reported here., Methods: Hospitalized adults with HAP/VAP proven or suspected to be caused by a Gram-negative pathogen were randomized 1:1 to receive CAZ-AVI or meropenem for 7 to 14 days. The primary outcome was 28-day all-cause mortality in the intent-to-treat (ITT) population. Secondary outcomes included clinical cure at test of cure (TOC) in the ITT and microbiological ITT (micro-ITT) populations, and safety and tolerability throughout the study., Results: hundred seventy randomized patients received treatment and were included in the ITT population (CAZ-AVI, n = 436; meropenem, n = 434). CAZ-AVI was noninferior to meropenem for the primary end point (28-day all-cause mortality; ITT) based on the prespecified 10% noninferiority margin (CAZ-AVI, 9.6%; meropenem, 8.3%; difference, 1.5%; 95% confidence interval [CI], -2.4% to 5.3%) and for the clinical cure end point in the ITT population based on a prespecified -10% noninferiority margin (CAZ-AVI, 67.2%; meropenem, 69.1%; difference, -1.9%; 95% CI, -8.1% to 4.3%). Clinical cure rates at TOC for patients infected with CAZ-nonsusceptible pathogens were similar (CAZ-AVI, 75.5%; meropenem, 71.2%; micro-ITT). Safety data were consistent with established safety profiles for both agents., Conclusions: CAZ-AVI provides an important new treatment option for HAP/VAP due to Gram-negative pathogens, including CAZ-nonsusceptible strains.

Avibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options. Selection and validation of the ceftazidime-avibactam dosage regimen was guided by an iterative process of population pharmacokinetic (PK) modelling, whereby population PK models for ceftazidime and avibactam were developed using PK data from clinical trials and updated periodically. These models were used in probability of target attainment (PTA) simulations using joint pharmacodynamic (PD) targets for ceftazidime and avibactam derived from preclinical data. Joint PTA was calculated based on the simultaneous achievement of the individual PK/PD targets (50% free time above the ceftazidime-avibactam MIC for ceftazidime and free time above a critical avibactam threshold concentration of 1 mg/liter for avibactam). The joint PTA analyses supported a ceftazidime-avibactam dosage regimen of 2,000 + 500 mg every 8 h by 2-h intravenous infusion for patients with creatinine clearance (CL CR ) >50 ml/min across all approved indications and modified dosage regimens for patients with CL CR ≤50 ml/min. Subgroup simulations for individual phase 3 patients showed that the dosage regimen was robust, with high target attainment (>95%) against MICs ≤8 mg/liter achieved regardless of older age, obesity, augmented renal clearance, or severity of infection. This review summarizes how the approved ceftazidime-avibactam dosage regimens were developed and validated using PK/PD targets, population PK modeling, and PTA analyses., (Copyright © 2019 American Society for Microbiology.)

The compound hazard effects of multiple process cascades severely affect Chilean river systems and result in a large variety of disturbances on their ecosystems and alterations of their hydromorphologic regimes leading to extreme impacts on society, environment and infrastructure. The acute, neo-tectonically pre-determined susceptibility to seismic hazards, the widespread volcanic activity, the increasing glacier retreat and the continuous exposure to forest fires clearly disturb entire riverine systems and concur to trigger severe floods hazards. With the objective to refine the understanding of such cascading processes and to prospect feasible flood risk management strategies in such a rapidly changing environment we first classify the large river basins according to a set of disturbances (i.e. volcanic eruptions, earthquakes, glacier lake outburst floods, wild fires and mass movements). Then, we describe emblematic cases of process cascades which affected specific Chilean drainage basins and resulted in high losses as tangible examples of how the cascading processes may unfold in other river basins with similar characteristics. As an attempt to enrich the debate among management authorities and academia in Chile, and elsewhere, on how to sustainably manage river systems, we: a) highlight the pivotal need to determine the possible process cascades that may profoundly alter the system and b) we suggest to refine hazard and risk assessments accordingly, accounting for the current and future exposure. We advocate, finally, for the adoption of holistic approaches promoting anticipatory adaptation which may result in resilient system responses., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Geomorphic strain markers accumulating the effects of many earthquake cycles help to constrain the mechanical behaviour of continental rift systems as well as the related seismic hazards. In the Corinth Rift (Greece), the unique record of onshore and offshore markers of Pleistocene ~100-ka climate cycles provides an outstanding possibility to constrain rift mechanics over a range of timescales. Here we use high-resolution topography to analyse the 3D geometry of a sequence of Pleistocene emerged marine terraces associated with flexural rift-flank uplift. We integrate this onshore dataset with offshore seismic data to provide a synoptic view of the flexural deformation across the rift. This allows us to derive an average slip rate of 4.5-9.0 mm·yr -1 on the master fault over the past ~610 ka and an uplift/subsidence ratio of 1:1.1-2.4. We reproduce the observed flexure patterns, using 3 and 5-layered lithospheric scale finite element models. Modelling results imply that the observed elastic flexure is produced by coseismic slip along 40-60° planar normal faults in the elastic upper crust, followed by postseismic viscous relaxation occurring within the basal lower crust or upper mantle. We suggest that such a mechanism may typify rapid localised extension of continental lithosphere.

In mid-2004, anthropogenically induced changes in water quality of the Río Cruces wetland, a Ramsar site located in southern Chile (ca. 40°S), enhanced the resuspension of iron-enriched sediments, which were subsequently deposited over the most abundant aquatic macrophyte of the wetland (Egeria densa Planch. 1849). This event triggered the formation of brownish, necrotic patches and increased iron contents in the leaves and stems of E. densa, which contributed to a significant demise of the plant within the wetland. In this study, we estimate the recovery time as a proxy for resilience of this macrophyte at organismal and population levels. Macro- and micro-optical characteristics, as well as iron contents in tissues of E. densa, were documented in four time windows (2004, 2008, 2012, and 2014). In addition, the size of the macrophyte population and its spatial occurrence were monitored from 2008 to 2016 across 36 study sites within the wetland. Our results suggest necrotic patches and high iron contents in E. densa persisted at least until 2008. After 2013, a significant increase in the spatial occurrence of E. densa was observed within the wetland, reaching full recovery of the population during 2015. The health of plant tissues and iron contents in leaves and stems showed recovery period close to 4 years, while the recovery of the spatial occurrence of E. densa took approximately 9 years. While the monitoring of plant health was not performed on a strict annual basis, the recovery rates estimated here are slower than those described for other macrophytes. This finding might reflect the long-lasting effects of the disturbance from 2004 and the interaction with biotic processes, such as foraging by waterbirds recolonizing the Río Cruces wetland. These results show that full recovery of E. densa was achieved through a cascade of effects starting with abiotic factors (water quality) and passing through physiological and individual levels, to finally reach the population level. A key aspect of this response is the invasive nature of the macrophyte, which likely contributed to its recovery as a consequence of improved water quality. Less successful macrophyte species in other systems may not reach the specific population recovery, and become subdominant species instead, or even be eradicated from the wetland either as the result of herbivory or due to competition with other macrophytes.

Objectives: To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L)., Methods: A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study., Results: The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L., Conclusions: The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

Background: Osteomyelitis is a challenging infection that can involve 4-6 weeks of intravenous (IV) antibiotics. Dalbavancin, approved for acute bacterial skin and skin structure infections, has potent activity against gram-positive pathogens. This study assessed the efficacy and safety of dalbavancin as a 2-dose regimen for osteomyelitis., Methods: This study was a randomized, open-label, comparator-controlled trial in adults with a first episode of osteomyelitis defined by clinical symptoms, radiologic findings, and elevated C-reactive protein. Patients were randomized 7:1 to dalbavancin (1500 mg IV on days 1 and 8) or standard of care (SOC) for osteomyelitis (oral or IV) per investigator judgment for 4-6 weeks. The primary endpoint was clinical response at day 42, defined as recovery without need for additional antibiotics in the clinically evaluable (CE) population. Clinical response was also assessed at day 21, 6 months, and 1 year., Results: Eighty patients were randomized to dalbavancin (n = 70) or SOC (n = 10). All had baseline debridement; Staphylococcus aureus was the most common pathogen (60% of patients). Clinical cure at day 42 was seen in 65/67 (97%) and 7/8 (88%) patients in the dalbavancin group and SOC group in the CE population, respectively. Clinical response was similar in the dalbavancin group at day 21 (94%), 6 months, and 1 year (96%). Treatment-emergent adverse events occurred in 10 patients in the dalbavancin group; no patient discontinued treatment due to an adverse event., Conclusions: A 2-dose regimen of weekly dalbavancin is effective and well tolerated for the treatment of osteomyelitis in adults., Clinical Trials Registration: NCT02685033.

Great megathrust earthquakes arise from the sudden release of energy accumulated during centuries of interseismic plate convergence. The moment deficit (energy available for future earthquakes) is commonly inferred by integrating the rate of interseismic plate locking over the time since the previous great earthquake. But accurate integration requires knowledge of how interseismic plate locking changes decades after earthquakes, measurements not available for most great earthquakes. Here we reconstruct the post-earthquake history of plate locking at Guafo Island, above the seismogenic zone of the giant 1960 (M w  = 9.5) Chile earthquake, through forward modeling of land-level changes inferred from aerial imagery (since 1974) and measured by GPS (since 1994). We find that interseismic locking increased to ~70% in the decade following the 1960 earthquake and then gradually to 100% by 2005. Our findings illustrate the transient evolution of plate locking in Chile, and suggest a similarly complex evolution elsewhere, with implications for the time- and magnitude-dependent probability of future events.

In 2004 migration and mortality for unknown reasons of the herbivorous Black necked swan (Cygnus melancorhyphus (Molina, 1782)) occurred within the Río Cruces wetland (southern Chile), a Ramsar Site and nature sanctuary. Before 2004, this wetland hosted the largest breeding population of this water bird in the Neotropic Realm. The concurrent decrease in the spatial occurrence of the aquatic plant Egeria densa Planch. 1849 - the main food source of swans - was proposed as a cause for swan migration and mortality. Additionally, post-mortem analyses carried out on swans during 2004 showed diminished body weight, high iron loads and histopathological abnormalities in their livers, suggesting iron storage disease. Various hypotheses were postulated to describe those changes; the most plausible related to variations in water quality after a pulp mill located upstream the wetland started to operate in February 2004. Those changes cascaded throughout the stands of E. densa whose remnants had high iron contents in their tissues. Here we present results of a long-term monitoring program of the wetland components, which show that swan population abundance, body weights and histological liver conditions recovered to pre-disturbance levels in 2012. The recovery of E. densa and iron content in plants throughout the wetland, also returned to pre-disturbance levels in the same 8-year time period. These results show the temporal scale over which resilience and natural restoring processes occur in wetland ecosystems of temperate regions such as southern Chile., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The etiology, epidemiology, treatment patterns, and clinical outcomes of neonatal and pediatric pneumonia patients in China are not well reported. This retrospective chart review study aimed to describe such information among neonatal (0 to 27 days) and pediatric (28 days to <18 years) pneumonia patients in two regions of China., Methods: Electronic medical records of pneumonia hospitalizations (aged <18 years) admitted between 2008 and 2013 from four hospitals under Guangdong Provincial Hospital of Chinese Medicine (Southern China) and between 2010 and 2014 at Peking University People's Hospital (Beijing, Northern China) were reviewed., Results: The average age of neonatal hospitalizations in Beijing (n=92) was 3.5 days. The mean length of hospital stay was 11.2 days, and no deaths occurred. Staphylococcus epidermidis was the most common bacteria found in Beijing patients, whereas Mycoplasma pneumoniae was the most common bacteria found in Guangdong patients. The average age of pediatric hospitalizations was 3.3 (±3.1) and 6.5 (±5.6) years in Guangdong (n=3,046) and Beijing (n=222), respectively. The mean length of hospital stay was 17.4 and 5.8 days, and overall mortality rates were 0.2% and 0.5%., Conclusion: The findings revealed a low level of bacterial isolation and hence microbiological diagnoses. There was a low level of in-hospital mortality due to pneumonia, and the majority of hospitalizations were discharged from hospital, suggesting that current practice was generally effective. Neonatal hospitalizations were greater than pediatric hospitalizations in Beijing along with disparity in bacterial profile when compared with Guangdong, intending a need to improve neonatal pneumonia prophylaxis and selection of appropriate treatment., Competing Interests: Disclosure JW, HX, and JH are employees of AstraZeneca. DM and JG are former employees of AstraZeneca. ZW, XL, and ZC received institutional/research grant funding from AstraZeneca for the conduct of the study. The authors report no other conflicts of interest in this work.

Background: Data describing epidemiology, clinical outcomes and treatment patterns, of hospitalised patients with pneumonia in China are limited. We aimed to describe such information among adult pneumonia patients in southern and northern China., Methods: We retrospectively reviewed electronic medical records of pneumonia patients aged ≥18 years, hospitalized between 2008 and 2013 at Guangdong Provincial Hospital of Chinese Medicine (n=3,636), southern China, and between 2010 and 2014 at Peking University People's Hospital, Beijing (n=1,689), northern China, in order to collect data on patient demographics, microbiology, clinical outcomes and treatment and resistance patterns., Results: The mean (SD) age of patients was 60.0 (21.4) and 64.4 (18.4) years in Guangdong and Beijing, respectively. Mean length of hospital stay was 12.1 and 20.8 days, and overall mortality was 2.9% and 8.0%, respectively. Gram-negative bacilli were most frequently isolated, predominantly Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa . Infection with these bacteria was associated with unfavourable clinical outcomes, and the antibiotic resistance among these bacteria increased between 2008-2010 and 2011-2013 in both regions of China. The treatment and choice of antibiotics slightly varied between the two regions based on the susceptible pathogens identified among their populations., Conclusions: Of the pathogens identified, Staphylococcus aureus infection (particularly the methicillin-resistant S. aureus ) was associated with poor clinical outcomes; however antibiotic resistance among S. aureus generally decreased during the study data collection periods. Also, disease severity was greater in Beijing as compared with Guangdong, and this may be associated with higher microbiological diagnosis rate and higher frequency of initial antibiotic modification among Beijing populations., Competing Interests: Conflicts of Interest: Jesus Gonzalez and Judith Hackett were employees of AstraZeneca at the time of the study. The remaining authors declare that they have no conflicts of interest.

The April 1st 2014 Iquique earthquake (MW 8.1) occurred along the northern Chile margin where the Nazca plate is subducted below the South American continent. The last great megathrust earthquake here, in 1877 of Mw ~8.8 opened a seismic gap, which was only partly closed by the 2014 earthquake. Prior to the earthquake in 2013, and shortly after it we compared data from leveled benchmarks, deployed campaign GPS instruments, continuous GPS stations and estimated sea levels using the upper vertical level of rocky shore benthic organisms including algae, barnacles, and mussels. Land-level changes estimated from mean elevations of benchmarks indicate subsidence along a ~100-km stretch of coast, ranging from 3 to 9 cm at Corazones (18°30'S) to between 30 and 50 cm at Pisagua (19°30'S). About 15 cm of uplift was measured along the southern part of the rupture at Chanabaya (20°50'S). Land-level changes obtained from benchmarks and campaign GPS were similar at most sites (mean difference 3.7±3.2 cm). Higher differences however, were found between benchmarks and continuous GPS (mean difference 8.5±3.6 cm), possibly because sites were not collocated and separated by several kilometers. Subsidence estimated from the upper limits of intertidal fauna at Pisagua ranged between 40 to 60 cm, in general agreement with benchmarks and GPS. At Chanavaya, the magnitude and sense of displacement of the upper marine limit was variable across species, possibly due to species-dependent differences in ecology. Among the studied species, measurements on lithothamnioid calcareous algae most closely matched those made with benchmarks and GPS. When properly calibrated, rocky shore benthic species may be used to accurately measure land-level changes along coasts affected by subduction earthquakes. Our calibration of those methods will improve their accuracy when applied to coasts lacking pre-earthquake data and in estimating deformation during pre-instrumental earthquakes.

Background: We conducted a meta-analysis of clinical trials of adults hospitalized with pneumonia outcomes research team (PORT) risk class 3-4 community-acquired pneumonia (CAP) receiving ceftaroline fosamil versus ceftriaxone., Methods: Three Phase III trials (clinicaltrials.gov registration numbers NCT00621504, NCT00509106 and NCT01371838) including 1916 hospitalized patients with CAP randomized 1:1 to empirical ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (1-2 g every 24 h) for 5-7 days were included in the meta-analysis. Primary outcome was clinical response at the test-of-cure visit (8-15 days after end of treatment) in the PORT risk class 3-4 modified ITT (MITT) and clinically evaluable (CE) populations. Data were tested for heterogeneity (χ(2) test) and, if not significant, results were pooled and OR and 95% CI constructed. A logistic regression analysis assessed factors impacting cure rate and treatment interactions., Results: Clinical cure rates in each trial consistently favoured ceftaroline fosamil versus ceftriaxone, with no evidence of heterogeneity. In the meta-analysis, ceftaroline fosamil was superior to ceftriaxone in the MITT (OR: 1.66; 95% CI 1.34, 2.06; P < 0.001) and CE (OR: 1.65; 95% CI 1.26, 2.16; P < 0.001) populations. Results were consistent across various patient- and disease-related factors including patients' age and PORT score. Prior antimicrobial use within 96 h of starting study treatment was associated with diminished differences in cure rates between treatments., Conclusions: Ceftaroline fosamil was superior to ceftriaxone for empirical treatment of adults hospitalized with CAP. Receipt of prior antimicrobial therapy appeared to diminish the observed treatment effect., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Several small studies have suggested that the percutaneous method of peritoneal dialysis (PD) catheter insertion is effective and has a lower complication rate than surgical techniques (open, laparoscopic or peritoneoscopic), although no randomized, controlled study has compared these methods. Our objective was to compare percutaneous PD catheter insertion vs surgical placement in terms of 1-year catheter survival, catheter dysfunction, fluid leak and incidence of peritonitis., Methods: We searched Medline for English-language literature from 1966 through June 2014, along with national conference proceedings and reference lists of all included publications to identify relevant studies. Inclusion criteria were having a measure of catheter survival at 1 year, catheter dysfunction, peritonitis rate per patient-month or fluid leak as outcomes. Studies were excluded if they were not in English or if they included pediatric patients. Random effects models were used to derive the pooled risk ratios, differences in patency and their variations., Results: Thirteen studies with a total of 2,681 subjects met the inclusion criteria. There was no significant difference in 1-year catheter survival in percutaneous vs surgical PD catheter placement (relative risk [RR] = 0.81; 95% confidence interval [CI]: 0.59-1.11, p = 0.19). Catheter dysfunction also did not differ significantly between the groups (pooled odds ratio [OR] = 0.86; 95% CI: 0.57-1.29, p = 0.46). The prevalence of peritoneal fluid leak also was similar for percutaneous and surgical groups (OR = 1.10; 95% CI: 0.58-2.09, p = 0.77). However, there was a significant lower incidence of peritonitis among those with percutaneous placement (incidence rate ratio [IRR] = 0.77; 95% CI: 0.62-0.96, p = 0.02). Significant heterogeneity was detected across studies (I2 = 78.4%, p&lt;0.0001)., Conclusions: Our results suggest that there is no significant difference in catheter survival between percutaneous and surgical placement of PD catheters. Whether there are significant benefits from percutaneous placement in terms of peritonitis rates requires further robust studies. These findings have significant implications for future design of clinical trials in the placement of PD catheters and the delivery of dialysis-related services.

Vegetated dunes are recognized as important natural barriers that shelter inland ecosystems and coastlines suffering daily erosive impacts of the sea and extreme events, such as tsunamis. However, societal responses to erosion and shoreline retreat often result in man-made coastal defence structures that cover part of the intertidal and upper shore zones causing coastal squeeze and habitat loss, especially for upper shore biota, such as dune plants. Coseismic uplift of up to 2.0 m on the Peninsula de Arauco (South central Chile, ca. 37.5º S) caused by the 2010 Maule earthquake drastically modified the coastal landscape, including major increases in the width of uplifted beaches and the immediate conversion of mid to low sandy intertidal habitat to supralittoral sandy habitat above the reach of average tides and waves. To investigate the early stage responses in species richness, cover and across-shore distribution of the hitherto absent dune plants, we surveyed two formerly intertidal armoured sites and a nearby intertidal unarmoured site on a sandy beach located on the uplifted coast of Llico (Peninsula de Arauco) over two years. Almost 2 years after the 2010 earthquake, dune plants began to recruit, then rapidly grew and produced dune hummocks in the new upper beach habitats created by uplift at the three sites. Initial vegetation responses were very similar among sites. However, over the course of the study, the emerging vegetated dunes of the armoured sites suffered a slowdown in the development of the spatial distribution process, and remained impoverished in species richness and cover compared to the unarmoured site. Our results suggest that when released from the effects of coastal squeeze, vegetated dunes can recover without restoration actions. However, subsequent human activities and management of newly created beach and dune habitats can significantly alter the trajectory of vegetated dune development. Management that integrates the effects of natural and human induced disturbances, and promotes the development of dune vegetation as natural barriers can provide societal and conservation benefits in coastal ecosystems.

Background: Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia., Methods: In this international, randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV acute community-acquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5-7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8-15 days after last dose of study drug) in the clinically evaluable population. Non-inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of -10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838., Findings: Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9·9%, 95% CI 2·8-17·1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data., Interpretation: Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III-IV community-acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population., Funding: AstraZeneca., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

AZD5847, a novel oxazolidinone with an MIC of 1 μg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular Mycobacterium tuberculosis. Oral administration of AZD5847 to mice infected with M. tuberculosis H37Rv in a chronic-infection model resulted in a 1.0-log10 reduction in the lung CFU count after 4 weeks of treatment at a daily area under the concentration-time curve (AUC) of 105 to 158 μg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success in an acute-infection model was an AUC for the free, unbound fraction of the drug/MIC ratio of ≥ 20. The percentage of time above the MIC in all of the efficacious regimens was 25% or greater., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Treatment of tuberculosis (TB) is impaired by the long duration and complexity of therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with combination chemotherapies. Oxazolidinones offer a potential new class of TB drugs, and linezolid-the only currently approved oxazolidinone-has proven highly effective against extensively drug-resistant (XDR) TB in experimental trials. However, widespread use of linezolid is prohibited by its significant toxicities. AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with AZD5847 are superior to those obtained with linezolid. Moreover, the efficacy of AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that AZD5847 may function well in combination therapies. AZD5847 appears to function similarly to linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of AZD5847 in both in vitro and animal models as well is in human clinical trials.

Sex-biased dispersal (SBD) is common in many vertebrates, including primates. However, dispersal patterns in New World primates may vary among closely related taxa or populations in different local environments. Here, we test for SBD in an endangered New World primate, the Central American Squirrel Monkey (Saimiri oerstedii citrinellus). Previous studies of behavioral ecology suggest predominantly female dispersal in S.o. oerstedii in the Southern Pacific region of Costa Rica. However, our genetic data do not support strongly female-biased dispersal in S.o. citrinellus in the Central Pacific region. Our tests for SBD using microsatellite data including comparisons of isolation-by-distance, AI(c) , and F(ST) values between males and females were not significant. Also, we found greater population genetic structure in mitochondrial markers than in microsatellite markers, indicative of predominantly male dispersal. We conclude that both sexes disperse in S.o. citrinellus, and that males probably disperse over longer distances. We discuss how spatial and temporal variation among local populations should be taken into account when studying dispersal patterns and especially sex bias., (© 2011 Wiley Periodicals, Inc.)

Deciphering ecological effects of major catastrophic events such as earthquakes, tsunamis, volcanic eruptions, storms and fires, requires rapid interdisciplinary efforts often hampered by a lack of pre-event data. Using results of intertidal surveys conducted shortly before and immediately after Chile's 2010 M(w) 8.8 earthquake along the entire rupture zone (ca. 34-38°S), we provide the first quantification of earthquake and tsunami effects on sandy beach ecosystems. Our study incorporated anthropogenic coastal development as a key design factor. Ecological responses of beach ecosystems were strongly affected by the magnitude of land-level change. Subsidence along the northern rupture segment combined with tsunami-associated disturbance and drowned beaches. In contrast, along the co-seismically uplifted southern rupture, beaches widened and flattened increasing habitat availability. Post-event changes in abundance and distribution of mobile intertidal invertebrates were not uniform, varying with land-level change, tsunami height and coastal development. On beaches where subsidence occurred, intertidal zones and their associated species disappeared. On some beaches, uplift of rocky sub-tidal substrate eliminated low intertidal sand beach habitat for ecologically important species. On others, unexpected interactions of uplift with man-made coastal armouring included restoration of upper and mid-intertidal habitat seaward of armouring followed by rapid colonization of mobile crustaceans typical of these zones formerly excluded by constraints imposed by the armouring structures. Responses of coastal ecosystems to major earthquakes appear to vary strongly with land-level change, the mobility of the biota and shore type. Our results show that interactions of extreme events with human-altered shorelines can produce surprising ecological outcomes, and suggest these complex responses to landscape alteration can leave lasting footprints in coastal ecosystems.

Pseudomonas aeruginosa pneumonia remains a most-difficult-to-treat nosocomial bacterial infection. We used mathematical modeling to identify drug exposure targets for meropenem in the epithelial lining fluid (ELF) of mice with Pseudomonas pneumonia driving substantial [2 to 3 log(10) (CFU/g)] killing and which suppressed resistant subpopulation amplification. We bridged to humans to estimate the frequency with which the largest licensed meropenem dose would achieve these exposure targets. Cell kills of 2 and 3 log(10) (CFU/g) and resistant subpopulation suppression were mediated by achieving time > MIC in ELF of 32%, 50%, and 50%. Substantial variability in meropenem's ability to penetrate into ELF of both mice and humans was observed. Penetration variability and high exposure targets combined to prevent even the largest licensed meropenem dose from achieving the targets at an acceptable frequency. Even a highly potent agent such as meropenem does not adequately suppress resistant subpopulation amplification as single-agent therapy administered at maximal dose and optimal schedule. Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans.

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of β-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC(ELF)/AUC(plasma) ratio. The range of AUC(ELF)/AUC(plasma) penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.

We observed vertically displaced coastal and river markers after the 27 February 2010 Chilean earthquake [moment magnitude (Mw) 8.8]. Land-level changes range between 2.5 and -1 meters, evident along an approximately 500-kilometers-long segment identified here as the maximum length of coseismic rupture. A hinge line located 120 kilometers from the trench separates uplifted areas, to the west, from subsided regions. A simple elastic dislocation model fits these observations well; model parameters give a similar seismic moment to seismological estimates and suggest that most of the plate convergence since the 1835 great earthquake was elastically stored and then released during this event.

Objective: The carbapenems are broad-spectrum beta-lactam antibiotics with activity against most organisms encountered in the pediatric intensive care unit (PICU). In anticipation of their increased use in critically ill children, we measured the effect of sustained meropenem use on the pattern of Gram-negative bacillus colonization in patients admitted to a tertiary care PICU., Design: : Prospective preintervention/postintervention comparison., Setting: Medical/surgical PICU., Patients: Consecutive PICU admissions over 2.5 yrs., Interventions: After a 6-mo baseline period, all children with serious infections admitted to the PICU during the subsequent 2 yrs were administered meropenem. The incidence of colonization by Gram-negative bacilli resistant to one of a battery of broad-spectrum parenteral agents, and by organisms resistant specifically to meropenem, during the baseline period was compared with the period of preferred meropenem use., Results: During the period of preferred meropenem use, the amount of meropenem used increased >seven-fold, whereas the use of other advanced generation beta-lactams was reduced by nearly 80%. The mean prevalence of colonization by antibiotic-resistant bacilli in general was not statistically altered during the period of meropenem preference (7.3 organisms/100 patient-days, vs. 9.4 organisms/100 patient-days at baseline, p < 0.09). The prevalence of colonization by Gram-negative organisms resistant specifically to meropenem was 0.61 organisms/100 patient-days during the baseline period vs. 1.04 organisms/100 patient-days during the period of meropenem preference (p < 0.30). The incidence of nosocomial infections did not change, and the prevalence of nosocomial infections caused by meropenem-resistant organisms was always <1% of all admissions during the period of meropenem preference., Conclusion: There was no statistically detectable effect on the prevalence of colonization by Gram-negative organisms resistant to one or more classes of broad-spectrum parenteral antibiotics, or to colonization by organisms resistant specifically to meropenem, when meropenem was the preferred antibiotic in a PICU.