In vitro activity of sulopenem and comparator agents against Enterobacterales and anaerobic clinical isolates collected during the SENTRY Antimicrobial Surveillance Program.

OBJECTIVES: Physicians must leverage several factors when making antibiotic therapy decisions, including route of administration and duration of therapy. Oral administration provides several potential advantages including increased accessibility, prevention of hospitalizations and earlier discharges. Sulopenem-a broad-spectrum, synthetic penem ß-lactam agent-uniquely possesses both oral and IV formulations along with noted stability among antimicrobial-resistant subsets. This study evaluated the in vitro activity of sulopenem and comparator agents against contemporary Enterobacterales and anaerobic clinical isolates predominantly from patients with bloodstream, intra-abdominal and urinary tract infections. METHODS: A contemporary collection of 1647 Enterobacterales and 559 anaerobic isolates was assembled from medical centres in Europe and the USA. Isolates were susceptibility tested using the CLSI reference methods: broth microdilution for Enterobacterales and agar dilution for anaerobes. RESULTS: Sulopenem demonstrated potent in vitro antimicrobial activity (MIC50/90, 0.03/0.25 mg/L) against Enterobacterales isolates regardless of infection type, inhibiting 99.2% of isolates at ≤1 mg/L. This activity was conserved against resistant phenotypes including ESBL-phenotype Escherichia coli (MIC50/90, 0.03/0.06 mg/L) and ESBL-phenotype Klebsiella pneumoniae (MIC50/90, 0.06/1 mg/L). Sulopenem maintained activity against ciprofloxacin-, nitrofurantoin- and trimethoprim/sulfamethoxazole-non-susceptible subsets (MIC50/90, 0.03-0.06/0.12-0.5 mg/L). Against anaerobic isolates, sulopenem (98.9% inhibited at ≤4 mg/L) and meropenem [98.4% susceptible (CLSI)] were the most active compounds tested. CONCLUSIONS: The potent in vitro activity of sulopenem against this large collection of recent Enterobacterales and anaerobic clinical isolates from multiple infection types supports its further clinical evaluation in the treatment of intra-abdominal and urinary tract infections.

Reduction of Escherichia coli O157:H7 in Finishing Cattle Fed Corn Genetically Modified to Produce Increased Concentrations of Alpha Amylase in the Corn Kernel.

Cattle are recognized as the principal reservoir for Escherichia coli O157:H7 and preharvest food safety efforts often focus on decreasing shedding of this pathogen in cattle feces. Enogen® corn (EC; Syngenta Seeds, LLC) is genetically modified to produce enhanced concentrations of α-amylase in the corn kernel endosperm. Research has demonstrated improvements in feed efficiency for cattle fed EC and research has not yet explored whether improved digestion impacts foodborne pathogen populations in cattle. Therefore, this study explored effects of finishing diets containing EC on Escherichia coli O157:H7 prevalence in cattle. A 2 × 2 factorial experiment was conducted with steers (n = 960) fed diets consisting of 2 types of silage (EC or Control) and grain (EC or Control), fed daily ad libitum. Steers were grouped into 12 blocks by incoming body weight, blocks were randomly assigned to one of four pens, and pens were randomly assigned to one diet. Cattle were sampled using rectoanal mucosal swabs in cohorts of 298-337 cattle per day, for a total of 3 sampling days (15-16 days apart). Escherichia coli O157:H7 prevalence rates ranged from not detected (0/75) to 10.0% (8/80) depending on sampling day. Tests for the silage × corn interaction, and the main effects of silage and corn, were not significant (p > 0.05); however, EC reduced the odds of Escherichia coli O157:H7 prevalence by 43% compared to the control corn diet (p = 0.07). Diets containing EC tended to decrease Escherichia coli O157:H7 prevalence in feedlot cattle; however, this reduction was not significant. Before a conclusion can be drawn about impact of EC on Escherichia coli O157:H7 in cattle, further research is necessary to (1) determine if this tendency is due to increased alpha amylase activity and (2) elucidate impact on Escherichia coli O157:H7 prevalence and concentration, as well as a possible mechanism of action.

Understanding the patient experience in hepatocellular carcinoma: a qualitative patient interview study.

PURPOSE: This study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development. METHODS: Patients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0-10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews. RESULTS: Interviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience. CONCLUSION: Patients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.

Understanding the patient experience of chronic kidney disease stages 2-3b: a qualitative interview study with Kidney Disease Quality of Life (KDQOL-36) debrief.

BACKGROUND: Qualitative patient interviews and patient-reported outcome instruments are important tools to understand the patient experience of disease. The aim of this study was to use patient interviews to identify concepts relevant and important to patients living with chronic kidney disease (CKD) stages 2-3b, develop a comprehensive conceptual model of the patient experience and debrief the Kidney Disease Quality of Life 36-item instrument (KDQOL-36) for patients with CKD stages 2-3b. METHODS: Concept elicitation interviews were conducted with patients with CKD stages 2-3b to identify signs/symptoms and impacts most relevant and important to patients (i.e., 'salient' concepts) and develop a conceptual model for the disease. Based on the salient concepts identified in the interviews, new items were proposed to supplement the KDQOL-36. Cognitive debriefing was performed to evaluate the KDQOL-36 and the additional items. RESULTS: A total of 31 patients were interviewed in this study (22 for concept elicitation and 15 for cognitive debriefing). The interviews identified 56 concepts (33 signs/symptoms and 23 impacts), 17 of which had not been identified in a previous literature review. Four signs/symptoms ('fatigue/lack of energy/tiredness', 'sleep problems', 'increased urination [including nocturia]' and 'swelling in legs/ankles/feet') and two impacts ('anxiety/worry' and 'general negative emotional/mental impact') were identified as salient. Of the salient signs/symptoms, three were not covered by the KDQOL-36 (sleep problems, increased urination and swelling in legs/ankles/feet) and were represented during cognitive debriefing interviews through four additional items (trouble falling asleep, trouble staying asleep, increased urination [including nocturia] and swelling in legs/ankles/feet) generated in the style of the KDQOL-36. All patients found the KDQOL-36 plus the four additional items relevant, and the majority found them clear. CONCLUSIONS: By identifying previously unknown concepts and augmenting the understanding of which are most important to patients, a comprehensive conceptual model was developed for patients who have CKD stages 2-3b. This study also demonstrates the suitability of the KDQOL-36 for patients who have CKD stages 2-3b and provides suggestions for how the instrument could be further developed to more comprehensively capture patient experience.

Influence of titration of antiseizure medications on treatment selection: Results of an online survey with clinicians in the United States.

INTRODUCTION: Most antiseizure medications (ASM) need to be titrated before the optimal dose is achieved. Titration can last several weeks to months. We assessed the impact titration schedules have on ASM treatment-related decisions in the United States (US). METHODS: An online survey was conducted with different healthcare providers (HCPs) in the US involved in the treatment and management of patients with epilepsy. The survey contained three sections: the first section with screening questions; the second on key factors that influence a HCP's decision-making when selecting treatments for different types of seizures and different treatment lines; and the third on the HCP's knowledge and perceptions regarding ASM titration for the treatment of patients with epilepsy. RESULTS: One-hundred and fifty HCPs (63% neurologists) completed the survey. Most HCPs considered titration schedule to be important, with only 1-3% of HCPs, depending on type of seizure, considering the titration schedule to be "not important at all" when prescribing therapy. Healthcare providers' acceptance of titration increased with shorter durations (≥50% accepted titration periods of ≤2 weeks), and lower number of tablets/capsules per dose (≥50% accepted ≤3 tablets/capsules per dose), doses (≥50% accepted ≤2 doses/day), and steps (≥50% accepted ≤3 steps/dose change). Most HCPs (68-91% depending on type of seizure) considered a titration duration of 6 or more weeks only somewhat acceptable or somewhat or highly unacceptable. Almost all HCPs selected "somewhat familiar", "familiar", or "very familiar" as the attribute that best defines their knowledge level of titration, with only 4% selecting "a little familiar". While 87% of HCPs agreed or strongly agreed that they could easily understand titration schedules, only 27% of them agreed or strongly agreed that patients could easily understand titration schedules and 58% of HCPs considered that adhering to the titration schedule was difficult for patients. Most HCPs agreed or strongly agreed that a complex or long titration schedule renders it difficult to achieve their treatment objectives. CONCLUSIONS: Healthcare providers take into account the duration and complexity of the titration period in their ASM prescribing decision-making and prefer shorter and simpler titration schedules, particularly for patients who are experiencing convulsive seizures and starting monotherapy. There was a clear difference between the HCP's belief in their own ability to understand a titration schedule, and their belief that the patient would be able to follow the titration schedule appropriately.

In vitro Activity of Ceftaroline Against an International Collection of Kingella kingae Isolates Recovered From Carriers and Invasive Infections.

BACKGROUND: Improvements in blood culture techniques and molecular-based diagnostics have led to increased recognition of Kingella kingae as an invasive human pathogen causing bacteremia, septic arthritis, osteomyelitis and endocarditis in young children. Serious disease and potentially life-threatening complications of infection due to K. kingae necessitate timely identification and appropriate antimicrobial therapy. Ceftaroline is a fifth-generation broad spectrum cephalosporin that possesses activity against Gram-negative and Gram-positive pathogens similar to third-generation cephalosporins, but also includes methicillin-resistant Staphylococcus aureus . This study reports the in vitro activity of ceftaroline and comparator agents against an international collection of K. kingae isolates. METHODS: A collection of 308 K. kingae isolates was obtained primarily from children with bacteremia, endocarditis, osteoarticular infections or from asymptomatic pediatric carriers. Isolates were tested for antibiotic susceptibility using Clinical and Laboratory Standard Institute broth microdilution methodology and screened for ß-lactamase production using a nitrocefin chromogenic test. RESULTS: Ceftaroline inhibited all K. kingae isolates at ≤0.06 mg/L (MIC 50/90 , 0.015/0.03 mg/L). Ceftaroline MICs were similar to results with ceftriaxone (MIC 50/90 , 0.015/0.015 mg/L), meropenem (MIC 50/90 , 0.015/0.015 mg/L) and ampicillin-sulbactam (MIC 50/90 , 0.06/0.06 mg/L). Ceftaroline MICs were slightly lower than MICs for cefuroxime and amoxicillin/clavulanate (MIC 50/90 , 0.06/0.12 mg/L). MICs were high for clindamycin (MIC 50/90 , 2/4 mg/L) and oxacillin (MIC 50/90 , 4/8 mg/L). Sixteen isolates (5.2%) yielded a positive nitrocefin test indicating production of ß-lactamase; ceftaroline demonstrated equivalent MICs against ß-lactamase - positive and ß-lactamase - negative strains (MIC 50/90 , 0.015/0.3 mg/L). CONCLUSIONS: The potent activity of ceftaroline against this large international collection of K. kingae isolates supports further clinical evaluation in children.

Impact of the Probiotic Organism Megasphaera elsdenii on Escherichia coli O157:H7 Prevalence in Finishing Cattle.

Feedlot cattle commonly shed the foodborne pathogen Escherichia coli O157:H7 in their feces. Megasphaera elsdenii (ME), a lactic acid-utilizing bacterium, is commonly administered to cattle to avoid lactate accumulation in the rumen and to control ruminal acidosis. The impact of administering ME on foodborne pathogen prevalence, specifically E. coli O157:H7, has not been explored. The purpose of this study was to quantify E. coli O157:H7 prevalence in finishing cattle administered ME. Cattle (n = 448) were assigned to treatments in a randomized complete block design with repeated measurements over two sampling periods. Treatments were arranged as a 2 × 2 factorial containing: ruminally protected lysine (RPL; included for a complementary study) fed at 0% or 0.45% of diet dry matter; with or without ME. Freeze-dried ME was administered as an oral drench (1 × 1010 CFU/steer on day one) and then top dressed onto basal diets (1 × 107 CFU/steer) daily thereafter. Rectoanal mucosal swabs (RAMS) were obtained from animals before harvest to determine the E. coli O157:H7 prevalence. The inclusion of RPL (P = 0.2136) and ME (P = 0.5012) did not impact E. coli O157:H7 prevalence, and RPL was not included in any significant interactions (P > 0.05). A significant interaction was observed between ME and sampling period (P = 0.0323), indicating that the effect of ME on E. coli O157:H7 prevalence varied over the sampling period. A diet containing ME reduced the odds of E. coli O157:H7 prevalence by 50% during sampling period 1 (8.0% and 14.7% for cattle with and without ME, respectively) and increased the odds by 23% during sampling period 2 (10.8% and 8.9% for cattle with and without ME, respectively). Administering ME in cattle diets did not impact E. coli O157:H7 in feedlot cattle. This is the first study to investigate the use of ME as a preharvest food safety intervention in cattle, and additional research is necessary to determine the efficacy.

Living with heart failure: patient experiences and implications for physical activity and daily living.

AIMS: Heart failure (HF) substantially limits the ability of patients to engage in physical activities. A detailed understanding of how patients experience these limitations is required to develop valid and sensitive measures for use in clinical research. This qualitative study was designed to provide a thorough description of how HF patients experience physical activity limitations in their daily lives. METHODS AND RESULTS: Semi-structured interviews were conducted with 40 HF patients. Interview transcripts were coded with the aim of identifying key aspects of physical activity. Patients were divided between HF with preserved ejection fraction (n = 21, 52.5%) and HF with reduced ejection fraction (n = 19, 47.5%); the majority of patients were New York Heart Association Class II (n = 22, 52.5%) or Class III (n = 16, 40.0%). Relevant physical activity themes, including mobility and broader daily function areas, were identified. The most frequently reported mobility limitations involved difficulty walking (up a steep incline, up steps, and long distances), limited walking speed, difficulty standing for long periods of time, and difficulty carrying and lifting objects. These limitations were principally related to three HF symptoms: dyspnoea, tiredness/fatigue, and peripheral oedema. Patients adapted to their symptoms and related mobility limitations in several ways, including taking rests during an activity, doing an activity more slowly, and avoiding/refraining from an activity altogether. The broader daily function areas most commonly impacted by the mobility limitations were housework, exercising or playing sports, and going shopping. CONCLUSIONS: Heart failure patients report numerous physical activity limitations. These specific mobility and daily function areas can be measured using clinical outcome assessments (e.g. patient-reported outcomes and performance outcomes) in clinical trials and observational research. Accelerometry can be used to contribute to a holistic picture of patient functioning by passively collecting this type of data.

Genotypic and Phenotypic Characterization of Antimicrobial Resistance Profiles in Non-typhoidal Salmonella enterica Strains Isolated From Cambodian Informal Markets.

Non-typhoidal Salmonella enterica is a pathogen of global importance, particularly in low and middle-income countries (LMICs). The presence of antimicrobial resistant (AMR) strains in market environments poses a serious health threat to consumers. In this study we identified and characterized the genotypic and phenotypic AMR profiles of 81 environmental S. enterica strains isolated from samples from informal markets in Cambodia in 2018-2019. AMR genotypes were retrieved from the NCBI Pathogen Detection website (https://www.ncbi.nlm.nih.gov/pathogens/) and using ResFinder (https://cge.cbs.dtu.dk/services/) Salmonella pathogenicity islands (SPIs) were identified with SPIFinder (https://cge.cbs.dtu.dk/services/). Susceptibility testing was performed by broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) standard guidelines M100-S22 using the National Antimicrobial Resistance Monitoring System (NARMS) Sensititre Gram Negative plate. A total of 17 unique AMR genes were detected in 53% (43/81) of the isolates, including those encoding tetracycline, beta-lactam, sulfonamide, quinolone, aminoglycoside, phenicol, and trimethoprim resistance. A total of 10 SPIs (SPI-1, 3-5, 8, 9, 12-14, and centisome 63 [C63PI]) were detected in 59 isolates. C63PI, an iron transport system in SPI-1, was observed in 56% of the isolates (n = 46). SPI-1, SPI-4, and SPI-9 were present in 13, 2, and 5% of the isolates, respectively. The most common phenotypic resistances were observed to tetracycline (47%; n = 38), ampicillin (37%; n = 30), streptomycin (20%; n = 16), chloramphenicol (17%; n = 14), and trimethoprim-sulfamethoxazole (16%; n = 13). This study contributes to understanding the AMR genes present in S. enterica isolates from informal markets in Cambodia, as well as support domestic epidemiological investigations of multidrug resistance (MDR) profiles.

Revealing ferroelectric switching character using deep recurrent neural networks.

The ability to manipulate domains underpins function in applications of ferroelectrics. While there have been demonstrations of controlled nanoscale manipulation of domain structures to drive emergent properties, such approaches lack an internal feedback loop required for automatic manipulation. Here, using a deep sequence-to-sequence autoencoder we automate the extraction of latent features of nanoscale ferroelectric switching from piezoresponse force spectroscopy of tensile-strained PbZr0.2Ti0.8O3 with a hierarchical domain structure. We identify characteristic behavior in the piezoresponse and cantilever resonance hysteresis loops, which allows for the classification and quantification of nanoscale-switching mechanisms. Specifically, we identify elastic hardening events which are associated with the nucleation and growth of charged domain walls. This work demonstrates the efficacy of unsupervised neural networks in learning features of a material's physical response from nanoscale multichannel hyperspectral imagery and provides new capabilities in leveraging in operando spectroscopies that could enable the automated manipulation of nanoscale structures in materials.

Machine Detection of Enhanced Electromechanical Energy Conversion in PbZr0.2 Ti0.8 O3 Thin Films.

Many energy conversion, sensing, and microelectronic applications based on ferroic materials are determined by the domain structure evolution under applied stimuli. New hyperspectral, multidimensional spectroscopic techniques now probe dynamic responses at relevant length and time scales to provide an understanding of how these nanoscale domain structures impact macroscopic properties. Such approaches, however, remain limited in use because of the difficulties that exist in extracting and visualizing scientific insights from these complex datasets. Using multidimensional band-excitation scanning probe spectroscopy and adapting tools from both computer vision and machine learning, an automated workflow is developed to featurize, detect, and classify signatures of ferroelectric/ferroelastic switching processes in complex ferroelectric domain structures. This approach enables the identification and nanoscale visualization of varied modes of response and a pathway to statistically meaningful quantification of the differences between those modes. Among other things, the importance of domain geometry is spatially visualized for enhancing nanoscale electromechanical energy conversion.

Gut microbiome in health and disease: Linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases.

The gut microbiome comprises the collective genome of the trillions of microorganisms residing in our gastrointestinal ecosystem. The interaction between the host and its gut microbiome is a complex relationship whose manipulation could prove critical to preventing or treating not only various gut disorders, like irritable bowel syndrome (IBS) and ulcerative colitis (UC), but also central nervous system (CNS) disorders, such as Alzheimer's and Parkinson's diseases. The purpose of this review is to summarize what is known about the gut microbiome, how it is connected to the development of disease and to identify the bacterial and biochemical targets that should be the focus of future research. Understanding the mechanisms behind the activity and proliferation of the gut microbiome will provide us new insights that may pave the way for novel therapeutic strategies.

Investigation into the Efficacy of Bdellovibrio bacteriovorus as a Novel Preharvest Intervention To Control Escherichia coli O157:H7 and Salmonella in Cattle Using an In Vitro Model.

Cattle are an important reservoir for the foodborne pathogens Salmonella and Escherichia coli O157:H7; they frequently harbor these microorganisms in their digestive tracts and shed them in their feces. Thus, there is potential for contamination of cattle hides and, subsequently, carcasses. Interventions aimed at reducing or eliminating pathogen shedding preharvest will also reduce the likelihood of beef product contamination by these pathogens. Therefore, this study used an in vitro model to evaluate Bdellovibrio bacteriovorus, a gram-negative microorganism that preys upon other gram-negative microorganisms, as a preharvest intervention to control Salmonella and E. coli O157:H7. Rumen fluid and feces were inoculated with pansusceptible or antimicrobial-resistant strains of one pathogen. Control samples were treated with HEPES buffer, whereas experimental samples were exposed to HEPES buffer plus B. bacteriovorus. Salmonella and E. coli O157:H7 populations were quantified at 0, 24, 48, and 72 h. The most-probable-number (MPN) technique, followed by streaking onto xylose lysine Tergitol 4 agar, was used to determine Salmonella populations, whereas spread plating onto sorbitol MacConkey agar supplemented with cefixime and tellurite was employed to enumerate E. coli O157:H7. B. bacteriovorus reduced pansusceptible Salmonella in cattle feces by 2.02 Log MPN/g (P = 0.0005) and antimicrobial-resistant Salmonella by 3.79 (P < 0.0001) and 2.24 (P = 0.0013) Log MPN/g after 24 and 48 h, respectively, in comparison to control samples. Significant reductions were not observed for E. coli O157:H7 in rumen or feces. These data suggest that further investigation into B. bacteriovorus efficacy as a preharvest intervention to control Salmonella in cattle is warranted.