Assessment of Activity and Resistance Mechanisms to Cefepime in Combination with the Novel ß-Lactamase Inhibitors Zidebactam, Taniborbactam, and Enmetazobactam against a Multicenter Collection of Carbapenemase-Producing Enterobacterales.

The global distribution of carbapenemases such as KPC, OXA-48, and metallo-ß-lactamases (MBLs) gives cause for concern, as these enzymes are not inhibited by classical ß-lactamase inhibitors (BLIs). The current development of new inhibitors is one of the most promising highlights for the treatment of multidrug-resistant bacteria. The activity of cefepime in combination with the novel BLIs zidebactam, taniborbactam, and enmetazobactam was studied in a collection of 400 carbapenemase-producing Enterobacterales (CPE). The genomes were fully sequenced and potential mechanisms of resistance to cefepime/BLI combinations were characterized. Cefepime resistance in the whole set of isolates was 79.5% (MIC50/90 64/≥128mg/L). The cefepime/zidebactam and cefepime/taniborbactam combinations showed the highest activity (MIC50/90 ≤0.5/1 and ≤0.5/2 mg/L, respectively). Cefepime/zidebactam displayed high activity, regardless of the carbapenemase or extended-spectrum ß-lactamase (ESBL) considered (99% of isolates displayed MIC ≤2 mg/L). Cefepime/taniborbactam displayed excellent activity against OXA-48- and KPC-producing Enterobacterales and lower activity against MBL-producing isolates (four strains yielded MICs ≥16 mg/L: 2 NDM producers with an insertion in PBP3, one VIM-1 producer with nonfunctional OmpK35, and one IMP-8 producer). Cefepime/enmetazobactam displayed the lowest activity (MIC50/90 1/≥128 mg/L), with MICs ≥16 mg/L for 49 MBL producers, 40 OXA-48 producers (13 with amino acid changes in OmpK35/36, 4 in PBPs and 11 in RamR) and 25 KPC producers (most with an insertion in OmpK36). These results confirm the therapeutic potential of the new ß-lactamase inhibitors, shedding light on the activity of cefepime and BLIs against CPE and resistance mechanisms. The cefepime/zidebactam and cefepime/taniborbactam combinations are particularly highlighted as promising alternatives to penicillin-based inhibitors for the treatment of CPE.

Correlation and agreement between physical and ultrasound examination after a training session dedicated to the standardization of synovitis assessment in rheumatoid arthritis patients.

OBJECTIVES: Assessing disease activity in rheumatoid arthritis (RA) patients requires comprehensive quantification of tender and swollen joints. We aimed to evaluate the correlation and agreement between rheumatologists after a training session dedicated to the standardization of synovitis assessment and compare its performance with a reference imaging modality such as musculoskeletal ultrasonography (MSUS). METHODS: In this cross-sectional study, a total of 28 and 10 joints in RA patients were evaluated by physical examination and ultrasound (US), respectively. After participating in a training session, individual joint assessment for tenderness and swelling was performed by three rheumatologists. MSUS examination was performed separately by an experimented radiologist in a standardized manner, evaluating findings according to the Outcome Measures in Rheumatology Clinical Trial (OMERACT) guidelines. RESULTS: A total of 80 RA patients were included, with a mean Disease Activity Score based on 28 joints (DAS28)-ESR of 4.02. The interobserver overall agreement and concordance rate in a total of 2240 joints assessed was 81.7% (k = 0.449, p < 0.0001) for tender joints and 66% (k = 0.227, p < 0.0001) for swollen joints. The overall concordance rate was fair (Fleiss' kappa = 0.21, p = 0.027) with an overall agreement of 67.18% yet, more joints were found to be swollen by the US assessment, compared to the physical examination (43% vs 39%). CONCLUSION: In our study population, joint tenderness showed better interobserver agreement, correlation, and concordance rate than joint swelling. When comparing the US assessment to the physical examination, a fair overall concordance rate supports the need for the implementation of training sessions dedicated to standardization in rheumatology clinics.

Cost and burden of poor anticoagulation control with vitamin K antagonists in patients with nonvalvular atrial fibrillation in Spain.

INTRODUCTION AND OBJECTIVES: The aim of this analysis was to evaluate the burden and cost of complications due to poor anticoagulation control in patients with nonvalvular atrial fibrillation (NVAF) treated with vitamin K antagonists (VKA) in Spain. METHODS: An analytical model was used to estimate annual differences in ischemic stroke, major bleeding, deaths, costs, and potential years of life lost between patients with poor anticoagulation control (time in therapeutic range <65%) and adequate control (time in therapeutic range ≥ 65%) with a 1-year time horizon. Information on the target population (patients ≥ 65 years), event rates, and costs were obtained from national sources. Direct costs in euros (2018) were included from the perspective of the national health system (NHS) and direct and indirect costs from the societal perspective. A sensitivity analysis was performed with post-hoc data from the SPORTIF III/V trials. RESULTS: We analyzed a hypothetical cohort of 594 855 patients, 48.3% with poor anticoagulation control, with an increase of 2321 ischemic strokes, 2236 major bleeding events and 14 463 deaths, and an annual incremental cost between €29 578 306 from the NHS perspective and €75 737 451 from the societal perspective. The annual impact of mortality was 170 502 potential years of life lost. The results of the sensitivity analysis showed that the annual cost would reach €97 787 873 from the societal perspective. CONCLUSIONS: Poor anticoagulation control with AVK has a strong impact on loss of health and on increased spending for the NHS.

Correlation and agreement between physical and ultrasound examination after a training session dedicated to the standardization of synovitis assessment in rheumatoid arthritis patients

Abstract Objectives: Assessing disease activity in rheumatoid arthritis (RA) patients requires comprehensive quantification of tender and swollen joints. We aimed to evaluate the correlation and agreement between rheumatologists after a training session dedicated to the standardization of synovitis assessment and compare its performance with a reference imaging modality such as musculoskeletal ultrasonography (MSUS). Methods: In this cross-sectional study, a total of 28 and 10 joints in RA patients were evaluated by physical examination and ultrasound (US), respectively. After participating in a training session, individual joint assessment for tenderness and swelling was performed by three rheumatologists. MSUS examination was performed separately by an experimented radiologist in a standardized manner, evaluating findings according to the Outcome Measures in Rheumatology Clinical Trial (OMERACT) guidelines. Results: A total of 80 RA patients were included, with a mean Disease Activity Score based on 28 joints (DAS28)-ESR of 4.02. The interobserver overall agreement and concordance rate in a total of 2240 joints assessed was 81.7% (k = 0.449, p < 0.0001) for tender joints and 66% (k = 0.227, p < 0.0001) for swollen joints. The overall concordance rate was fair (Fleiss' kappa = 0.21, p = 0.027) with an overall agreement of 67.18% yet, more joints were found to be swollen by the US assessment, compared to the physical examination (43% vs 39%). Conclusion: In our study population, joint tenderness showed better interobserver agreement, correlation, and concordance rate than joint swelling. When comparing the US assessment to the physical examination, a fair overall concordance rate supports the need for the implementation of training sessions dedicated to standardization in rheumatology clinics.

Cost-Effectiveness Analysis of Apixaban Versus Edoxaban in Patients with Atrial Fibrillation for Stroke Prevention.

OBJECTIVE: Our objective was to assess the cost effectiveness of apixaban versus edoxaban in the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF) in Spain. METHODS: We customized a Markov model with ten health states to estimate the lifetime economic and clinical outcomes in 6-week cycles. The efficacy (clinical event rates per 100 patient-years) and safety data were derived from a pairwise indirect treatment comparison. The analysis was conducted from both the national health service (NHS) and societal perspectives, and included pharmaceutical costs (retail price plus value-added tax (VAT) and applicable national deductions) according to daily dosages (apixaban 10 mg (5 mg twice daily (bid)) and edoxaban 60 or 30 mg) and complications and disease-management costs, obtained from national databases. Utilities for quality-adjusted life-year (QALY) calculations reflected EuroQoL 5-Dimension scores in patients with AF. An annual discount rate of 3% was applied for costs (€, year 2019 values) and outcomes. RESULTS: In a 1000-patient cohort, apixaban 5 mg bid versus edoxaban 60 mg could avoid five strokes, six major bleedings and 29 clinically relevant non-major bleedings (CRNMBs). Compared with edoxaban 30 mg, apixaban could avoid 21 strokes and two SEs. An increase in bleedings was observed with apixaban (seven haemorrhagic strokes, 48 major bleedings and 17 CRNMBs). Apixaban yielded 0.04 additional QALYs compared with edoxaban 60 mg or 30 mg. Incremental costs/QALY were €9639.33 and €354.22 for apixaban versus edoxaban 60 mg and edoxaban 30 mg, respectively, from the NHS perspective and €7756.62 for apixaban versus edoxaban 60 mg from the societal perspective. Apixaban was dominant versus edoxaban 30 mg from the societal perspective. Sensitivity analyses confirmed the robustness of the model. CONCLUSIONS: This study suggests that apixaban 5 mg bid is a cost-effective alternative to edoxaban for stroke prevention in the AF population in Spain.

Life after per-oral endoscopic myotomy: long-term outcomes of quality of life and their association with Eckardt scores.

BACKGROUND AND AIMS: The clinical efficacy of per-oral endoscopic myotomy (POEM) has been commonly established by reduction in the Eckardt score (<3) after the procedure. However, achalasia can lead to significant impairment in the patient's quality of life that may go beyond the 4 classic achalasia symptoms as measured by the Eckardt score. The aims of our study were to evaluate the effect of POEM on short-term and long-term health-related quality of life (HRQOL) and to assess the association between HRQOL and Eckardt scores. METHODS: Single-center, prospective, cohort study of consecutive POEMs during a 3-year period. Eckardt and HRQOL scores as measured by the short-form survey questionnaire (SF-36) were obtained at baseline and at various intervals after POEM. Comparison of the mean scores was described by using univariate linear regression. The association between Eckardt scores and HRQOL were calculated by using a linear, mixed-model analysis. RESULTS: POEM was performed in 143 consecutive patients (54% male; mean ± standard deviation [SD] age, 56.9 ± 17.9 years). At long-term follow-up (mean 16.4 months, range 12-40), both the HRQOL baseline mental and physical component scores improved significantly from 61.5 ± 2.2 to 71.2 ± 3.6; (P < .021) and from 55.8 ± 2.2 to 63.6 ± 3.3; (P = < .034), respectively. Mixed-model analysis showed a significant association between Eckardt and all HRQOL scores (P < .001). CONCLUSION: POEM improved all dimensions of HRQOL as measured by the SF-36 survey at both short-term and long-term follow-up. A strong association was seen between Eckardt scores and all HRQOL domains. Further studies with the use of disease-specific HRQOL instruments are warranted. (Clinical trial registration number: NCT01832779.).

Ablación por radiofrecuencia en niños y adolescentes con taquicardia paroxística supraventricular, sin cardiopatía estructural / Radioablation for paroxysmal SVT without cardiopathy in children and adolescents

Introducción: la ablación transcatéter por radiofrecuencia constituye una alternativa terapéutica curativa para diferentes taquiarritmias cardíacas, evitando crisis reiteradas, así como el uso de fármacos antiarrítmicos en forma crónica, con un procedimiento menos agresivo y costoso que la cirugía. Este trabajo evalúa retrospectivamente nuestra experiencia con este método terapéutico en niños y adolescentes fuertemente sintomáticos, con taquicardia paroxística supraventricular y un corazón estructuralmente sano. Poblacion: costó de 56 pacientes consecutivos, con edades de 6 a 18 años (x: 13 ñ 3, X: 13) y taquicardias reiteradas a pesar del tratamiento antiarrítmico, 3 de los cuales presentaban, además, antecedentes de síncope y muerte súbita. Material y métodos: el diagnóstico electrofisiológico incluyó: taquicardia por reentrada AV, utilizando una vía accesoria, en 48 pacientes, de los cuales 34 tenían síndrome de Wolff-Parkinson-White y taquicardia reentrante nodal en 8. A continuación se procedió a realizar la ablación por radiofrecuencia. Resultados: la ablación fue primariamente exitosa en 52 pacientes (93 porciento). La duración total del procedimiento fue de 226 ñ 143 min, x: 210 minutos, el tiempo de radioscopia, 42 ñ 33 min, x: 40 min y el número de aplicaciones de radiofrecuencia, 4 ñ 3, x: 2 pulsos. Se presentaron complicaciones en sólo 3 casos (5,4 porciento). Durante un seguimiento de 0,5 a 7,5 años (3,3 ñ 1,7, X: 2,5), 10 pacientes sufrieron recidivas, repitiéndose exitosamente la ablación en 6 de ellos. El procedimiento fue considerado curativo en 48 de 56 pacientes (86 porciento). Conclusiones: nuestra experiencia con ablación por radiofrecuencia en esta población fue ampliamente satisfactoria, con alto índice de efectividad, escasa morbilidad y mortalidad nula