The Structural Role of N170 in Substrate-Assisted Deacylation in KPC-2 β-Lactamase.

The amino acid substitutions in Klebsiella pneumoniae carbapenemase 2 (KPC-2) that have arisen in the clinic are observed to lead to the development of resistance to ceftazidime-avibactam, a preferred treatment for KPC bearing Gram-negative bacteria. Specific substitutions in the omega loop (R164-D179) result in changes in the structure and function of the enzyme, leading to alterations in substrate specificity, decreased stability, and more recently observed, increased resistance to ceftazidime/avibactam. Using accelerated rare-event sampling well-tempered metadynamics simulations, we explored in detail the structural role of R164 and D179 variants that are described to confer ceftazidime/avibactam resistance.

Longitudinal Effects of Glucose-Lowering Medications on β-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

Objective: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and β-cell function.

Research Design And Methods: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points.

Structural role of K224 in taniborbactam inhibition of NDM-1.

Taniborbactam (TAN; VNRX-5133) is a novel bicyclic boronic acid β-lactamase inhibitor (BLI) being developed in combination with cefepime (FEP). TAN inhibits both serine and some metallo-β-lactamases. Previously, the substitution R228L in VIM-24 was shown to increase activity against oxyimino-cephalosporins like FEP and ceftazidime (CAZ).

An Open-Source 3D-Printed Hindlimb Stabilization Apparatus for Reliable Measurement of Stimulation-Evoked Ankle Flexion in Rat.

Currently there are numerous methods to evaluate peripheral nerve stimulation interfaces in rats, with stimulation-evoked ankle torque being one of the most prominent. Commercial rat ankle torque measurement systems and custom one-off solutions have been published in the literature. However, commercial systems are proprietary and costly and do not allow for customization.

Is the time right for a new initiative in mathematical modeling of the lower urinary tract? ICI-RS 2023.

Introduction: A session at the 2023 International Consultation on Incontinence - Research Society (ICI-RS) held in Bristol, UK, focused on the question: Is the time right for a new initiative in mathematical modeling of the lower urinary tract (LUT)? The LUT is a complex system, comprising various synergetic components (i.e., bladder, urethra, neural control), each with its own dynamic functioning and high interindividual variability.

Distinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination.

Tuberculosis remains an international health threat partly because of limited protection from pulmonary tuberculosis provided by standard intradermal vaccination with Bacillus of Calmette and Guérin (BCG); this may reflect the inability of intradermal vaccination to optimally induce pulmonary immunity. In contrast, respiratory Mycobacterium tuberculosis infection usually results in the immune-mediated bacillary containment of latent tuberculosis infection (LTBI). Here we present RNA-Seq-based assessments of systemic and pulmonary immune cells from LTBI participants and recipients of intradermal and oral BCG.

Structural basis of metallo-β-lactamase resistance to taniborbactam.

The design of inhibitors against metallo-β-lactamases (MBLs), the largest family of carbapenemases, has been a strategic goal in designing novel antimicrobial therapies. In this regard, the development of bicyclic boronates, such as taniborbactam (TAN) and xeruborbactam, is a major achievement that may help in overcoming the threat of MBL-producing and carbapenem-resistant Gram-negative pathogens. Of concern, a recent report has shown that New Delhi MBL-9 (NDM-9) escapes the inhibitory action of TAN by a single amino acid substitution with respect to New Delhi MBL-1 (NDM-1), the most widely disseminated MBL.

Can we improve techniques and patients' selection for nerve stimulation suitable for lower urinary tract dysfunctions? ICI-RS 2023.

Aims: Lower urinary tract dysfunctions (LUTD) are very common and, importantly, affect patients' quality of life (QoL). LUTD can range from urinary retention to urgency incontinence and includes a variety of symptoms. Nerve stimulation (NS) is an accepted widespread treatment with documented success for LUTD and is used widely.

Utilizing Ceftazidime/Avibactam Therapeutic Drug Monitoring in the Treatment of Neurosurgical Meningitis Caused by Difficult-to-Treat Resistant and KPC-Producing Enterobacterales.

Background: Central nervous system (CNS) infections caused by carbapenemase (KPC)-producing Enterobacterales and difficult-to-treat resistant (DTR) represent a formidable clinical challenge. Antimicrobial regimens that efficiently penetrate the cerebrospinal fluid (CSF) and achieve sufficient concentrations associated with microbiologic and clinical cure are limited. We evaluated therapy with ceftazidime-avibactam (CAZ-AVI) in order to guide precise dosing in the treatment of CNS infections.

Draft genome sequence of CRL 2244, a strain with strong killing effect on carbapenem-resistant .

We report here a draft genome assembly of CRL 2244, recovered from wastewater in Argentina. The genome has a size of 2,898,100 bp, with G + C content of 46.73%.

Reconnecting the Hand and Arm to the Brain: Efficacy of Neural Interfaces for Sensorimotor Restoration After Tetraplegia.

Background And Objectives: Paralysis after spinal cord injury involves damage to pathways that connect neurons in the brain to peripheral nerves in the limbs. Re-establishing this communication using neural interfaces has the potential to bridge the gap and restore upper extremity function to people with high tetraplegia. We report a novel approach for restoring upper extremity function using selective peripheral nerve stimulation controlled by intracortical microelectrode recordings from sensorimotor networks, along with restoration of tactile sensation of the hand using intracortical microstimulation.

The role of the plasmid-mediated fluoroquinolone resistance genes as resistance mechanisms in pediatric infections due to Enterobacterales.

Introduction: Fluoroquinolones (FQs) are not commonly prescribed in children, yet the increasing incidence of multidrug-resistant (MDR) Enterobacterales (Ent) infections in this population often reveals FQ resistance. We sought to define the role of FQ resistance in the epidemiology of MDR Ent in children, with an overall goal to devise treatment and prevention strategies.

Methods: A case-control study of children (0-18 years) at three Chicago hospitals was performed.

The directed evolution of NDM-1.

β-Lactam antibiotics are among the most frequently prescribed therapeutic agents. A common mechanism of resistance toward β-lactam antibiotics is the production of β-lactamases. These enzymes are capable of hydrolyzing the β-lactam bond, rendering the drug inactive.

Natural protein engineering in the Ω-loop: the role of Y221 in ceftazidime and ceftolozane resistance in -derived cephalosporinase.

A wide variety of clinically observed single amino acid substitutions in the Ω-loop region have been associated with increased minimum inhibitory concentrations and resistance to ceftazidime (CAZ) and ceftolozane (TOL) in -derived cephalosporinase and other class C β-lactamases. Herein, we demonstrate the naturally occurring tyrosine to histidine substitution of amino acid 221 (Y221H) in -derived cephalosporinase (PDC) enables CAZ and TOL hydrolysis, leading to similar kinetic profiles ( = 2.3 ± 0.

Military Medicine and Medical Research as a Source of Inspiration and Innovation to Solve National Security and Health Challenges in the 21st Century.

The history of military medicine and research is rife with examples of novel treatments and new approaches to heal and cure soldiers and others impacted by war's devastation. In the 21st century, new threats, like climate change, are combined with traditional threats, like geopolitical conflict, to create novel challenges for our strategic interests. Extreme and inaccessible environments provide heightened risks for warfighter exposure to dangerous bacteria, viruses, and fungi, as well as exposure to toxic substances and extremes of temperature, pressure, or both providing threats to performance and eroding resilience.

3D Printed Materials for Combating Antimicrobial Resistance.

Three-dimensional (3D) printing is a rapidly growing technology with a significant capacity for translational applications in both biology and medicine. 3D-printed living and non-living materials are being widely tested as a potential replacement for conventional solutions for testing and combating antimicrobial resistance (AMR). The precise control of cells and their microenvironment, while simulating the complexity and dynamics of an environment, provides an excellent opportunity to advance the modeling and treatment of challenging infections and other health conditions.

Exploring avibactam and relebactam inhibition of carbapenemase D179N variant: role of the Ω loop-held deacylation water.

carbapenemase-2 (KPC-2) presents a clinical threat as this β-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes. expressing KPC-2 D179Y acquired resistance to the ceftazidime/avibactam combination affecting both the β-lactam and the β-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other β-lactams tested.

Improving Referral Patterns for Bronchoscopic Lung Volume Reduction: A Quality Improvement Initiative.

Bronchoscopic lung volume reduction (BLVR) is a minimally invasive treatment option for patients with severe emphysema and hyperinflation refractory to optimal medical care. This therapy is effective in improving functional status and quality of life, underscoring the importance of identifying potential procedure candidates. To our knowledge, scalable strategies to improve the referral of advanced lung disease patients are lacking.

Correction: 2-Mercaptomethyl-thiazolidines use conserved aromatic-S interactions to achieve broad-range inhibition of metallo-β-lactamases.

[This corrects the article DOI: 10.1039/D0SC05172A.].