First evidence of a biomarker-based dose-response relationship in chronic pain using physiological closed-loop spinal cord stimulation.

BACKGROUND AND OBJECTIVES: In spinal cord stimulation (SCS) therapy, electricity is the medication delivered to the spinal cord for pain relief. In contrast to conventional medication where dose is determined by desired therapeutic plasma concentration, there is lack of equivalent means of determining dose delivery in SCS. In open-loop (OL) SCS, due to the dynamic nature of the epidural space, the activating electric field delivered is inconsistent at the level of the dorsal columns. Recent Food and Drug Administration guidance suggests accurate and consistent therapy delivered using physiologic closed-loop control (PCLC) devices can minimize underdosage or overdosage and enhance medical care. PCLC-based evoked compound action potential (ECAP)-controlled technology provides the ability to prescribe a precise stimulation dose unique to each patient, continuously measure neural activation, and objectively inform SCS therapy optimization. METHODS: Neurophysiological indicator metrics of therapy dose, usage above neural activation threshold, and accuracy of SCS therapy were assessed for relationship with pain reduction in over 600 SCS patients. RESULTS: Significant relationships between objective metrics and pain relief across the patient population are shown, including first evidence for a dose-response relationship in SCS. CONCLUSIONS: Higher dose, more time over ECAP threshold, and higher accuracy are associated with better outcomes across patients. There is potential to optimize individual patient outcomes based on unique objective measurable electrophysiological inputs.

Methods for SARS-CoV-2 hospital disinfection, in vitro observations.

Introduction: Escalation of chemical disinfection during the COVID-19 pandemic has raised occupational hazard concerns. Alternative and potentially safer methods such as ultraviolet-C (UVC) irradiation and ozone have been proposed, notwithstanding the lack of standardized criteria for their use in the healthcare environment. Aim: Compare the virucidal activity of 70% ethanol, sodium dichloroisocyanurate (NaDCC), chlorhexidine, ozonated water, UVC-222 nm, UVC-254 nm against three SARS-CoV-2 variants of concern cultured in vitro. Methods: Inactivation of three SARS-CoV-2 variants (alpha, beta, gamma) by the following chemical methods was tested: ethanol 70%, NaDCC (100 ppm, 500 ppm, 1000 ppm), chlorhexidine (2%, 1% and 0.5%), ozonated water 7 ppm. For irradiation, a je2Care 222nm UVC Lamp was compared to a Sylvania G15 UV254 nm lamp. Results: Viral inactivation by >3 log was achieved with ethanol, NaDCC and chlorhexidine. The minor virucidal effect of ozonated water was <1 log. Virus treatment with UVC-254 nm reduced viral activity by 1-5 logs with higher inactivation after exposure for 3 minutes compared to 6 seconds. For all three variants, under equivalent conditions, exposure to UVC-222 nm did not achieve time-dependent inactivation as was observed with treatment with UVC-254 nm. Conclusion: The virucidal activity on replication-competent SARS-CoV-2 by conventional chemical methods, including chlorhexidine at concentrations as low as 0.5%, was not matched by UVC irradiation, and to an even lesser extent by ozonated water treatment.

Modulation of Structure and Dynamics of Cardiac Troponin by Phosphorylation and Mutations Revealed by Molecular Dynamics Simulations.

Adrenaline acts on ß1 receptors in the heart muscle to enhance contractility, increase the heart rate, and increase the rate of relaxation (lusitropy) via activation of the cyclic AMP-dependent protein kinase, PKA. Phosphorylation of serines 22 and 23 in the N-terminal peptide of cardiac troponin I is responsible for lusitropy. Mutations associated with cardiomyopathy suppress the phosphorylation-dependent change. Key parts of troponin responsible for this modulatory system are disordered and cannot be resolved by conventional structural approaches. We performed all-atom molecular dynamics simulations (5 × 1.5 µs runs) of the troponin core (419 amino acids) in the presence of Ca2+ in the bisphosphorylated and unphosphorylated states for both wild-type troponin and the troponin C (cTnC) G159D mutant. PKA phosphorylation affects troponin dynamics. There is significant rigidification of the structure involving rearrangement of the cTnI(1-33)-cTnC interaction and changes in the distribution of the cTnC helix A/B angle, troponin I (cTnI) switch peptide (149-164) docking, and the angle between the regulatory head and ITC arm domains. The familial dilated cardiomyopathy cTnC G159D mutation whose Ca2+ sensitivity is not modulated by cTnI phosphorylation exhibits a structure inherently more rigid than the wild type, with phosphorylation reversing the direction of all metrics relative to the wild type.

Identification of antibiotic consumption targets for the management of Clostridioides difficile infection in hospitals- a threshold logistic modelling approach.

BACKGROUND: This study aims to demonstrate the utility of a threshold logistic approach to identifying thresholds for specific antibiotic use associated with Clostridioides difficile infection (CDI) in an English teaching hospital. METHODS: A combined approach of nonlinear modeling and logistic regression, named threshold logistic, was used to identify thresholds and risk scores in hospital-level antibiotic use associated with hospital-onset, healthcare-associated (HOHA) CDI cases. RESULTS: Using a threshold logistic regression approach, an incidence greater than 0.2645 cases/1000 occupied bed-days (OBD; 85th percentile) was determined as the cutoff rate to define a critical (high) incidence rate of HOHA CDI. Fluoroquinolones and piperacillin-tazobactam were found to have thresholds at 84.8 and 54 defined daily doses (DDD)/1000 OBD, respectively. Analysis of data allowed calculating risk scores for HOHA CDI incidence rates exceeding the 85th percentile, i.e. entering critical incidence level. The threshold-logistic model also facilitated performing 'what-if scenarios' on future values of fluoroquinolones and piperacillin-tazobactam use to understand how HOHA CDI incidence rates may be affected. CONCLUSION: Using threshold logistic analysis, critical incidence levels and antibiotic use targets to control HOHA CDI were determined. Threshold logistic models can be used to inform and enhance the effective design and implementation of antimicrobial stewardship programs.

Laboratory Surveillance, Quality Management, and Its Role in Addressing Antimicrobial Resistance in Africa: A Narrative Review.

AMR is a major public health concern that calls for extensive work and a multidisciplinary team approach. The high prevalence of infectious diseases in African nations leads to widespread antibiotic usage and eventual antimicrobial resistance, which has significant negative effects on people's health, the economy, and society. Additionally, inadequate or nonexistent antimicrobial drug regulations, inappropriate prescription practices, and restrictions on public health prevention initiatives such as immunization, water and sanitation, and sexual health may all contribute to the emergence of AMR. Despite the need for laboratory quality assurance, many African laboratories confront substantial difficulties in implementing efficient quality assurance programs. AMR surveillance in Africa is hampered by a lack of laboratory capacity, insufficient data collection and analysis, and poor stakeholder collaboration. Several initiatives and programs, including the World Health Organization's Global Antimicrobial Resistance and Use Surveillance System (GLASS), the Africa Centres for Disease Control and Prevention (Africa CDC) Antimicrobial Resistance Surveillance Network (AMRSNET), and the Fleming Fund, a UK government initiative aimed at tackling AMR in low- and middle-income countries, have been established to strengthen AMR surveillance in Africa and globally.

ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

Chlorhexidine Resistance or Cross-Resistance, That Is the Question.

Chlorohexidine (CHX) is a widely used biocide in clinical and household settings. Studies over the last few decades have reported CHX resistance in different bacterial species, but at concentrations well below those used in the clinical setting. Synthesis of these findings is hampered by the inconsistent compliance with standard laboratory procedures for biocide susceptibility testing. Meanwhile, studies of in vitro CHX-adapted bacteria have reported cross-resistance between CHX and other antimicrobials. This could be related to common resistance mechanisms of CHX and other antimicrobials and/or the selective pressure driven by the intensive use of CHX. Importantly, CHX resistance and cross-resistance to antimicrobials should be investigated in clinical as well as environmental isolates to further our understanding of the role of CHX in selection of multidrug resistance. Whilst clinical studies to support the hypothesis of CHX cross-resistance with antibiotics are currently lacking, we recommend raising the awareness of healthcare providers in a range of clinical disciplines regarding the potential adverse impact of the unfettered use of CHX on tackling antimicrobial resistance.

Evaluation of emerging NASH therapies: the impact of treatment efficacy profiles on long-term health outcomes.

Aim: Evaluations of nonalcoholic steatohepatitis (NASH) treatments require predicting lifetime outcomes from short-term clinical trials. Materials & methods: A Markov model with NASH fibrosis stages F0-F3, NASH resolution, compensated cirrhosis (F4/CC), and liver-related complication (LRC) states was developed using literature-based standard of care (SoC) data. Hypothetical efficacy profiles were defined affecting resolution (100%-increase), fibrosis improvement (100% increase), or fibrosis worsening (50% decrease). Results: For the SoC, 10-year LRC rates increased with baseline fibrosis stage (F1: 3.0%; F2: 9.8%; F3: 27.2%; F4/CC: 64.9%). The fibrosis worsening profile reduced predicted 10-year LRC rates (F1: 1.9%; F2: 6.5%; F3: 19.1%; F4/CC: 55.0%) more than the resolution and fibrosis improvement profiles (F1: 2.6%/2.6%; F2: 8.5%/8.3%; F3: 23.3%/23.0%; F4/CC: NA/59.0%). Scenario analyses considered alternative SoC progression, treatment efficacy and treatment-stopping rules. Conclusion: Potential NASH efficacy profiles have differing impacts on predicted long-term outcomes, providing insights for future stakeholders.

Many new treatments are being investigated for nonalcoholic steatohepatitis (NASH), a progressive and life-threatening disease often resulting in liver fibrosis (scarring) and advanced liver disease. The clinical value of these treatments and whether they are good value for money will depend on their ability to reduce the risk of advanced liver disease and subsequent liver transplantation. We developed a disease progression model which tracks survival and quality of life for two identical groups of NASH patients over their lifetimes. One group received a new hypothetical treatment for NASH while the other received current standard care. We used the model to estimate the potential health benefits of different hypothetical treatments for NASH. Our results suggest that treatments slowing fibrosis worsening may lead to greater long-term health benefits than treatments that improve NASH or improve existing fibrosis. These findings may provide insights to researchers involved in the development of new treatments for NASH.

Kinetics and Mechanisms of Hydrothermal Dehydration of Cyclic 1,2- and 1,4-Diols.

Hydrothermal dehydration is an attractive method for deoxygenation and upgrading of biofuels because it requires no reagents or catalysts other than superheated water. Although mono-alcohols cleanly deoxygenate via dehydration under many conditions, polyols such as those derived from saccharides and related structures are known to be recalcitrant with respect to dehydration. Here, we describe detailed mechanistic and kinetic studies of hydrothermal dehydration of 1,2- and 1,4-cyclohexanediols as model compounds to investigate how interactions between the hydroxyls can control the reaction. The diols generally dehydrate more slowly and have more complex reaction pathways than simple cyclohexanol. Although hydrogen bonding between hydroxyls is an important feature of the diol reactions, hydrogen bonding on its own does not explain the reduced reactivity. Rather, it is the way that hydrogen bonding influences the balance between the E1 and E2 elimination mechanisms. We also describe the reaction pathways and follow-up secondary reactions for the slower-dehydrating diols.

Large-Scale Distributed Training of Transformers for Chemical Fingerprinting.

Transformer models have become a popular choice for various machine learning tasks due to their often outstanding performance. Recently, transformers have been used in chemistry for classifying reactions, reaction prediction, physiochemical property prediction, and more. These models require huge amounts of data and localized compute to train effectively. In this work, we demonstrate that these models can successfully be trained for chemical problems in a distributed manner across many computers─a more common scenario for chemistry institutions. We introduce MFBERT: Molecular Fingerprints through Bidirectional Encoder Representations from Transformers. We use distributed computing to pre-train a transformer model on one of the largest aggregate datasets in chemical literature and achieve state-of-the-art scores on a virtual screening benchmark for molecular fingerprints. We then fine-tune our model on smaller, more specific datasets to generate more targeted fingerprints and assess their quality. We utilize a SentencePiece tokenization model, where the whole procedure from raw molecular representation to molecular fingerprints becomes data-driven, with no explicit tokenization rules.

Response: Sometimes we wish Chris and Sam had died of cancer! - a response to Commentaries on the May 2022 Debate.

The debate articles in CAMH Journal, May 2022, have received some responses from contributors who are well known for their anti-diagnosis views concerning borderline personality disorder (BPD). Within these responses, we had hoped to see these campaigners try to test their worldview against our tragic experiences but we have been sadly disappointed. Our daughters actually lived in the world these campaigners hope to construct: a world where professionals behave as if BPD does not exist, a world where NICE Guidance for BPD is therefore entirely ignored. That world led to our daughters' deterioration and deaths. We address the main arguments against diagnosis as we have come to understand them and end with a plea to channel the passions of this debate into a solution that would have helped Sam and Chris.

Identifying Targets for Antibiotic Use for the Management of Carbapenem-Resistant Acinetobacter baumannii (CRAb) in Hospitals-A Multi-Centre Nonlinear Time-Series Study.

Solutions are needed to inform antimicrobial stewardship (AMS) regarding balancing the access to effective antimicrobials with the need to control antimicrobial resistance. Theoretical and mathematical models suggest a non-linear relationship between antibiotic use and resistance, indicating the existence of thresholds of antibiotic use beyond which resistance would be triggered. It is anticipated that thresholds may vary across populations depending on host, environment, and organism factors. Further research is needed to evaluate thresholds in antibiotic use for a specific pathogen across different settings. The objective of this study is to identify thresholds of population antibiotic use associated with the incidence of carbapenem-resistant Acinetobacter baumannii (CRAb) across six hospital sites in Oman. The study was an ecological, multi-centre evaluation that involved collecting historical antibiotic use and CRAb incidence over the period from January 2015 to December 2019. By using non-linear time-series analysis, we identified different thresholds in the use of third-generation cephalosporins, piperacillin-tazobactam, aminoglycoside, and fluoroquinolones across participating hospitals. The identification of different thresholds emphasises the need for tailored analysis based on modelling data from each hospital. The determined thresholds can be used to set targets for each hospital AMS, providing a balance between access to these antibiotics versus controlling CRAb incidence.

Modulation of cardiac thin filament structure by phosphorylated troponin-I analyzed by protein-protein docking and molecular dynamics simulation.

Tropomyosin, controlled by troponin-linked Ca2+-binding, regulates muscle contraction by a macromolecular scale steric-mechanism that governs myosin-crossbridge-actin interactions. At low-Ca2+, C-terminal domains of troponin-I (TnI) trap tropomyosin in a position on thin filaments that interferes with myosin-binding, thus causing muscle relaxation. Steric inhibition is reversed at high-Ca2+ when TnI releases from F-actin-tropomyosin as Ca2+ and the TnI switch-peptide bind to the N-lobe of troponin-C (TnC). The opposite end of cardiac TnI contains a phosphorylation-sensitive ∼30 residue-long N-terminal peptide that is absent in skeletal muscle, and likely modifies these interactions in hearts. Here, PKA-dependent phosphorylation of serine 23 and 24 modulates Ca2+ and possibly switch-peptide binding to TnC, causing faster relaxation during the cardiac-cycle (lusitropy). The cardiac-specific N-terminal TnI domain is not captured in crystal structures of troponin or in cryo-EM reconstructions of thin filaments; thus, its global impact on thin filament structure and function is uncertain. Here, we used protein-protein docking and molecular dynamics simulation-based protocols to build a troponin model that was guided by and hence consistent with the recent seminal Yamada structure of Ca2+-activated thin filaments. We find that when present on thin filaments, phosphorylated Ser23/24 along with adjacent polar TnI residues interact closely with both tropomyosin and the N-lobe of TnC during our simulations. These interactions would likely bias tropomyosin to an off-state positioning on actin. In situ, such enhanced relaxation kinetics would promote cardiac lusitropy.

Debate: "The-Diagnosis-That-Must-Not-Be-Named" - Professionals' fear of BPD is failing their patients.

Borderline personality disorder (BPD) in Child and Adolescent Mental Health Services (CAMHS) seems to be the "Voldemort Diagnosis" - it must not be named! We believe this is misguided and dangerous. Failure to inform patients and carers of the potential for this diagnosis disempowers them. Everyone has a right to research and understand their own condition. The absence of honest diagnoses leaves young people feeling "mad and bad" and losing trust in professionals' ability to help them. Complex Post Traumatic Stress Disorder is not a suitable substitute diagnosis (at least not for our daughters). Failure to identify BPD symptoms in young people means CAMHS services are not investing in the treatments needed by these young people - often leading to the kind of inpatient stays that Guidelines from the National Institute for Health and Care Excellence (NICE) warn against - and to further deterioration.

Lipid21: Complex Lipid Membrane Simulations with AMBER.

We extend the modular AMBER lipid force field to include anionic lipids, polyunsaturated fatty acid (PUFA) lipids, and sphingomyelin, allowing the simulation of realistic cell membrane lipid compositions, including raft-like domains. Head group torsion parameters are revised, resulting in improved agreement with NMR order parameters, and hydrocarbon chain parameters are updated, providing a better match with phase transition temperature. Extensive validation runs (0.9 µs per lipid type) show good agreement with experimental measurements. Furthermore, the simulation of raft-like bilayers demonstrates the perturbing effect of increasing PUFA concentrations on cholesterol molecules. The force field derivation is consistent with the AMBER philosophy, meaning it can be easily mixed with protein, small molecule, nucleic acid, and carbohydrate force fields.

Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial.

Importance: Chronic pain is debilitating and profoundly affects health-related quality of life. Spinal cord stimulation (SCS) is a well-established therapy for chronic pain; however, SCS has been limited by the inability to directly measure the elicited neural response, precluding confirmation of neural activation and continuous therapy. A novel SCS system measures the evoked compound action potentials (ECAPs) to produce a real-time physiological closed-loop control system. Objective: To determine whether ECAP-controlled, closed-loop SCS is associated with better outcomes compared with fixed-output, open-loop SCS at 24 months following implant. Design, Setting, and Participants: The Evoke study was a double-blind, randomized, controlled, parallel arm clinical trial with 36 months of follow-up. Participants were enrolled from February 2017 to 2018, and the study was conducted at 13 US investigation sites. SCS candidates with chronic, intractable back and leg pain refractory to conservative therapy, who consented, were screened. Key eligibility criteria included overall, back, and leg pain visual analog scale score of 60 mm or more; Oswestry Disability Index score of 41 to 80; stable pain medications; and no previous SCS. Analysis took place from October 2020 to April 2021. Interventions: ECAP-controlled, closed-loop SCS was compared with fixed-output, open-loop SCS. Main Outcomes and Measures: Reported here are the 24-month outcomes of the trial, which include all randomized patients in the primary and safety analyses. The primary outcome was a reduction of 50% or more in overall back and leg pain assessed at 3 and 12 months (previously published). Results: Of 134 randomized patients, 65 (48.5%) were female and the mean (SD) age was 55.2 (10.6) years. At 24 months, significantly more closed-loop than open-loop patients were responders (≥50% reduction) in overall pain (53 of 67 [79.1%] in the closed-loop group; 36 of 67 [53.7%] in the open-loop group; difference, 25.4% [95% CI, 10.0%-40.8%]; P = .001). There was no difference in safety profiles between groups (difference in rate of study-related adverse events: 6.0 [95% CI, -7.8 to 19.7]). Improvements were also observed in health-related quality of life, physical and emotional functioning, and sleep, in parallel with opioid reduction or elimination. Objective neurophysiological measurements substantiated the clinical outcomes and provided evidence of activation of inhibitory pain mechanisms. Conclusions and Relevance: ECAP-controlled, closed-loop SCS, which elicited a more consistent neural response, was associated with sustained superior pain relief at 24 months, consistent with the 3- and 12-month outcomes.

The evolution of ICER's review process for new medical interventions and a critical review of economic evaluations (2018-2019): how stakeholders can collaborate with ICER to improve the quality of evidence in ICER's reports.

BACKGROUND: Since its inception in 2006, the Institute for Clinical and Economic Review (ICER) has rapidly gained influence on drug pricing and reimbursement decisions despite historical resistance to the use of cost-effectiveness thresholds in the US health care system. Although patient groups, physicians, and pharmaceutical manufacturers voiced their concerns about the potential negative effects of increased use of ICER's assessments on patient access to innovative medications, there is little guidance and consensus on how the stakeholders should collaborate with ICER to ensure that its reviews reflect the best clinical and economic evidence. OBJECTIVES: To (1) summarize the evolution of ICER's evaluation procedure, scope, and topics; (2) evaluate the effectiveness of stakeholder engagement approaches; and (3) inform stakeholders of their potential role in collaborating with ICER in estimating the cost-effectiveness of new interventions. METHODS: Publicly available ICER evaluations from 2008 to 2019 were systematically reviewed. Changes in evaluation procedures, scope, and topics were summarized. For evaluations that occurred in 2018 (n = 12) and 2019 (n = 8), key characteristics were extracted from 172 letters documenting interactions between ICER and all stakeholders who provided comments to draft reports. Stakeholder suggestions were analyzed in terms of their effectiveness indicated by ICER's reconsideration of its original cost-effectiveness analysis approach. RESULTS: The number of ICER evaluations increased consistently from 2 to 12 per year between 2008 and 2018 but declined to 8 in 2019. Stakeholder opportunity to engage with ICER increased from 1 to 3 per evaluation between 2008 and 2015. ICER initially focused on reviewing general treatment strategies but shifted its focus to specific pharmaceuticals and medical devices in 2014. In 2018 and 2019, 30% of 172 stakeholder letters resulted in a revision in the base-case analysis (49 comments in 2018, 23 in 2019); nearly half of comments in these letters included specific alternative data or a published article to rationalize recommendations. Other common types of suggestions that resulted in ICER's base-case analysis revisions included comments relating to inconsistent methods used to derive model inputs across different treatments (12/49 in 2018, 5/23 in 2019); clinical justifications (12/49 in 2018, 0/23 in 2019); and justifications based on patient perspectives (1/49 in 2018, 5/23 in 2019). These revisions rarely affected ICER's conclusions on the cost-effectiveness of evaluated interventions. Among the 20 assessments that involved 172 stakeholder engagements in 2018 and 2019, only 2% (n = 3) of the engagements (all from 2018) were associated with a change in the cost-effectiveness conclusion. CONCLUSIONS: Between 2018 and 2019, stakeholders leveraged ICER evaluations as opportunities to promote dialogue for better understanding of the value of technologies. Actionable, evidence-based recommendations were accepted more often than other recommendations. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to disclose. Findings from this study were presented as a poster at Virtual ISPOR, May 17-20, 2021.

Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa.

The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.