Optimizing the dosing of vancomycin in patients receiving intermittent haemodialysis with low-flux filters, and the potential impact of dosing software.

AIM: Iterative approaches to vancomycin dosing (e.g., dosing when trough concentrations <15-20 mg/L) can be inadequate. Computer-guided dosing may be superior but has not been evaluated in patients with kidney failure receiving replacement therapy. We evaluated vancomycin concentrations using a hospital protocol and a pharmacokinetic software. We measured vancomycin clearance by the FX8 low-flux filter because data are absent. METHODS: We retrospectively reviewed records of adults with kidney failure requiring replacement therapy receiving vancomycin and dialysed with the FX8 low-flux filter, and calculated the proportion of pre-dialysis concentrations that were within, above or below a specified range. One and two-compartment models in the pharmacokinetic software were assessed by computing mean prediction error (MPE) and root mean square error (RMSE) of observed versus predicted concentrations. Vancomycin extracorporeal clearance was prospectively determined using the extraction method. RESULTS: In 24 patients (34 courses; 139 paired observed and predicted concentrations), 62/139 (45%) pre-dialysis concentrations were 15-25 mg/L, 29/139 (21%) were above, and 48/139 (35%) were below. MPE for the one-compartment model was -0.2 mg/L, RMSE 5.3 mg/L. MPE for the two-compartment model was 2.0 mg/L, RMSE 5.6 mg/L. Excluding the first paired concentrations, the subsequent MPE (n = 105) using one-compartment model was -0.5 mg/L, RMSE 5.6 mg/L. The MPE for the two-compartment model was 2.1 mg/L, RMSE 5.8 mg/L. The median extracorporeal clearance was 70.7 mL/min (range: 10.3-130.3; n = 22). CONCLUSIONS: Vancomycin dosing was suboptimal and the pharmacokinetic software was not sufficiently predictive. These may improve with a loading dose. The substantial removal of vancomycin by low-flux filters is not accounted for by the models tested.

How to adjust drug doses in chronic kidney disease.

Drugs excreted by the kidney require dose reduction in chronic kidney disease. This adjustment depends on the severity of the disease and what proportion of the drug is eliminated by the kidneys The estimated glomerular filtration rate can generally be used to guide dose adjustment in patients with stable kidney function. However, the formula can be misleading in some patient subsets and other approaches are required At extremes of body mass, the estimated glomerular filtration rate can under- or overestimate kidney function. It may need to be adjusted for body surface area, particularly for drugs with a narrow therapeutic range or requiring a minimum concentration to be effective. Close monitoring of drug effect and toxicity is also needed and can be supported by therapeutic drug monitoring For short courses of drugs with a wide therapeutic index, dose adjustment may not be needed Alternative methods for quantifying kidney function include the Cockcroft-Gault formula (estimates creatinine clearance) or direct measures of glomerular filtration rate using exogenous isotope compounds. These are not commonly required

A proposed index of myocardial staining for vein of Marshall ethanol infusion: an Italian single-center experience.

BACKGROUND: Mitral isthmus (MI) conduction block is a fundamental step in anatomical approach treatment for persistent atrial fibrillation (PeAF). However, MI block is hardly achievable with endocardial ablation only. Retrograde ethanol infusion (EI) into the vein of Marshall (VOM) facilitates MI block. Fluorographic myocardial staining (MS) during VOM-EI could be helpful in predicting procedural alcoholization outcome even if its role is qualitatively assessed in the routine. The aim was to quantitatively assess MS during VOM-EI and to evaluate its association with MI block achievement. METHODS: Consecutive patients undergoing catheter ablation for PeAF at Fondazione Toscana Gabriele Monasterio (Pisa, Italy) from February 2022 to May 2023 were considered. Patients with identifiable VOM were included. A proposed index of MS (MSI) was retrospectively calculated in each included patient. Correlation of MSI with low-voltage zones (LVZ) extension after VOM-EI and its association with MI block achievement were assessed. RESULTS: In total, 42 patients out of 49 (85.8%) had an identifiable VOM. MI block was successfully achieved in 35 patients out of 42 (83.3%). MSI was significantly associated with the occurrence of MI block (OR 1.24 (1.03-1.48); p = 0.022). A higher MSI resulted in reduced ablation time (p = 0.014) and reduced radiofrequency applications (p = 0.002) to obtain MI block. MSI was also associated with MI block obtained by endocardial ablation only (OR 1.07 (1.02-1.13); p = 0.002). MSI was highly correlated with newly formed LVZ extension (r = 0.776; p = 0.001). CONCLUSIONS: In our study cohort, optimal MSI predicts MI block and facilitates its achievement with endocardial ablation only.

Disseminated Mycobacterium chelonae infection complicating rheumatoid arthritis: A case report and review of the literature.

INTRODUCTION: Rheumatoid arthritis (RA) may predispose patients to opportunistic infections-either from innate immune dysregulation, or as a result of immunosuppressant use to treat the RA. Particularly concerning opportunistic infections are those caused by non-tuberculous mycobacterial (NTM) organisms, the incidence of which has been increasing in epidemiological studies. Despite this, guidelines on the management of patients with RA who develop NTM infections are scarce, particularly with respect to immunosuppressant regimen modulation and duration of antibiotic therapy. CASE REPORT: Herein, we present a case of disseminated Mycobacterium chelonae infection, manifesting as arthralgia and cutaneous nodules. DISCUSSION: In addition, a review of the literature was conducted to Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines to identify similar cases in the literature-revealing that all RA-associated M. Chelonae infections occurred in immunosuppressed patients (the majority with corticosteroids or tumor necrosis factor inhibitors), and considerable heterogeneity in management approaches. Further research regarding risk factors, preventative approaches and best management of such NTM infections in vulnerable patients with RA is required in order to establish consensus guidelines and consistency.

Epidemiology, Modern Diagnostics, and the Management of Mucorales Infections.

Mucormycosis is an uncommon, yet deadly invasive fungal infection caused by the Mucorales moulds. These pathogens are a WHO-assigned high-priority pathogen group, as mucormycosis incidence is increasing, and there is unacceptably high mortality with current antifungal therapies. Current diagnostic methods have inadequate sensitivity and specificity and may have issues with accessibility or turnaround time. Patients with diabetes mellitus and immune compromise are predisposed to infection with these environmental fungi, but COVID-19 has established itself as a new risk factor. Mucorales also cause healthcare-associated outbreaks, and clusters associated with natural disasters have also been identified. Robust epidemiological surveillance into burden of disease, at-risk populations, and emerging pathogens is required. Emerging serological and molecular techniques may offer a faster route to diagnosis, while newly developed antifungal agents show promise in preliminary studies. Equitable access to these emerging diagnostic techniques and antifungal therapies will be key in identifying and treating mucormycosis, as delayed initiation of therapy is associated with higher mortality.

ß-Blockers to optimize peripheral oxygenation during extracorporeal membrane oxygenation: a case series.

OBJECTIVES: Veno-venous extracorporeal membrane oxygenation (ECMO) is a well-established therapy in patients affected by respiratory failure and unresponsive to conventional therapy. Despite technical innovations, some limitations still exist, the most important one being refractory hypoxemia. This problem is linked partially to the mixture between patients' blood and ECMO fully oxygenated blood. In the present work, the reduction of cardiac output was proposed for the treatment of refractory hypoxemia in patients with high-flow ECMO and high endogenous cardiac output. DESIGN: An observational study. SETTING: A university hospital. PARTICIPANTS: Three consecutive patients suffering from persisting severe hypoxemia despite high-flow ECMO and with concomitant high cardiac output (>7 L/min). INTERVENTION: A bolus dose of 500 µg/kg and a continuous infusion of esmolol was used and titrated to an SpO(2) >92%. MEASUREMENTS AND MAIN RESULTS: Esmolol administration was safe and highly beneficial in terms of peripheral oxygenation. PaO(2) increased from 54 to 90 mmHg, from 50 to 94 mmHg, and from 49 to 66 mmHg during the first 12 hours of esmolol treatment in the 3 patients. CONCLUSIONS: In selected septic, tachycardic patients with a high cardiac output, veno-venous ECMO, led to improvement of peripheral oxygenation with the addition of a short-acting ß-blocker infusion.

Anesthetic management of transcatheter aortic valve implantation with transaxillary approach.

OBJECTIVE: To describe the anesthetic management of transcatheter aortic valve implantation (TAVI) with the transaxillary approach. DESIGN: An observational cohort study. SETTING: Two university hospitals. PARTICIPANTS: Twenty-two patients with severe aortic stenosis (± regurgitation) at high risk for surgical valve replacement, with contraindications for transfemoral TAVI (81 ± 4.9 years; logistic EuroSCORE, 27% ± 16.9%). INTERVENTION: General anesthesia or local anesthesia plus sedation followed by postoperative care. MEASUREMENTS AND MAIN RESULTS: Local anesthesia plus sedation and general anesthesia were used in 14 and 8 patients, respectively. Two patients undergoing local anesthesia were monitored with transesophageal echocardiography and supported with noninvasive mask ventilation during the procedure. Main complications included hemodynamic instability requiring inotropes (2 patients), severe postimplant aortic regurgitation requiring immediate second valve-in-valve implantation (1 patient), valve embolization requiring open-valve surgery (1 patient), subclavian artery dissection compromising the flow to a mammary artery graft (1 patient), ascending aortic dissection (1 patient), stroke (2 patients), and atrioventricular block requiring pacemaker implantation (3 patients). Four patients experienced an increased (baseline value × 1.5) postoperative serum creatinine. Five patients required red blood cell tranfusions (2 units). Intensive care unit stay and hospital stay were 6 (4-23) hours and 8 (8-9) days, respectively. All patients were alive 30 days after the procedure. The 6-month mortality was 9%. CONCLUSIONS: Transaxillary TAVI is feasible in high-risk patients with aortic stenosis and peripheral vasculopathy. Nevertheless, severe procedural complications are possible, and anesthesiologists should be prepared to assist in the management of these conditions.

Evaluation of a Pilot Vancomycin Precision Dosing Advisory Service on Target Exposure Attainment Using an Interrupted Time Series Analysis.

This study evaluated the ability of a pilot therapeutic drug monitoring (TDM) Advisory Service to facilitate vancomycin therapeutic target attainment within a real-world clinical setting. The Service provided area under the concentration-time curve (AUC)-guided vancomycin dose recommendations, using Bayesian forecasting software and clinical expertise, to prescribers at an Australian hospital. A retrospective audit of intravenous vancomycin therapy (> 48 hours) in adults (≥ 18 years old) was undertaken over a 54-month period to evaluate attainment of established vancomycin pharmacokinetic/pharmacodynamic targets (AUC over 24 hours / minimum inhibitory concentration: 400-600) before (36-month period) and after (18-month period) Service implementation. Interrupted time series analysis was employed to evaluate monthly measures of the median proportion of therapy spent within the target range. Indices of time to target attainment were also assessed before and after Service implementation. The final cohort comprised 1,142 courses of vancomycin (816 patients); 835 courses (596 patients) and 307 courses (220 patients) administered before and after Service implementation, respectively. Prior to piloting the Service, the median proportion of time in the target range was 40.1% (95% CI, 34.3-46.0%); this increased by 10.4% (95% CI, 1.2-19.6%, P = 0.03) after the Service, and was sustained throughout the post-Service evaluation period. Post-Service target attainment at 48-72 hours after initiation of therapy was increased (7.8%, 95% CI, 1.3-14.3%, P = 0.02). The findings of this study provide evidence that a consultative TDM Service can facilitate attainment of vancomycin therapeutic targets; however, optimization of the Service may further improve the use of vancomycin.

1,4-Butanediol overdose mimicking toxic alcohol exposure.

Context: 1,4-butanediol (1,4-BD) is a gamma-hydroxybutyrate (GHB) analogue with a similarly narrow therapeutic window that is becoming a more common cause of recreational overdose. Reports of confirmed exposures are limited.Case details: A 44 year-old man who had consumed alcohol subsequently became unconscious after ingesting what was thought to be GHB. The presentation was not entirely consistent with GHB poisoning, including a longer duration of unconsciousness and features that mimicked toxic alcohol exposure including a high anion gap metabolic acidosis (HAGMA) and osmol gap. The patient was treated supportively with intubation, haemodiafiltration and intravenous ethanol until the diagnosis was refined using specific laboratory testing. The concentration of 1,4-BD was the highest reported in the literature and the outcome favourable.Discussion: This case highlights pharmacokinetic issues peculiar to 1,4-BD, including the interaction with ethanol which delays the onset of psychoactive effects from 1,4-BD's metabolite GHB, and dose-dependent pharmacokinetics. In overdose, 1,4-BD can induce a HAGMA and other features of toxic alcohol poisoning. Managing an unconscious patient with these features can prompt certain treatments until the diagnosis is refined, which can require specific laboratory testing to identify the culprit. The actual risk of toxic alcohol and other causes is adjusted on a case-by-case basis from the history of exposure and local epidemiology of substance use and poisoning.

A model selection approach to discover age-dependent gene expression patterns using quantile regression models.

BACKGROUND: It has been a long-standing biological challenge to understand the molecular regulatory mechanisms behind mammalian ageing. Harnessing the availability of many ageing microarray datasets, a number of studies have shown that it is possible to identify genes that have age-dependent differential expression (DE) or differential variability (DV) patterns. The majority of the studies identify "interesting" genes using a linear regression approach, which is known to perform poorly in the presence of outliers or if the underlying age-dependent pattern is non-linear. Clearly a more robust and flexible approach is needed to identify genes with various age-dependent gene expression patterns. RESULTS: Here we present a novel model selection approach to discover genes with linear or non-linear age-dependent gene expression patterns from microarray data. To identify DE genes, our method fits three quantile regression models (constant, linear and piecewise linear models) to the expression profile of each gene, and selects the least complex model that best fits the available data. Similarly, DV genes are identified by fitting and comparing two quantile regression models (non-DV and the DV models) to the expression profile of each gene. We show that our approach is much more robust than the standard linear regression approach in discovering age-dependent patterns. We also applied our approach to analyze two human brain ageing datasets and found many biologically interesting gene expression patterns, including some very interesting DV patterns, that have been overlooked in the original studies. Furthermore, we propose that our model selection approach can be extended to discover DE and DV genes from microarray datasets with discrete class labels, by considering different quantile regression models. CONCLUSION: In this paper, we present a novel application of quantile regression models to identify genes that have interesting linear or non-linear age-dependent expression patterns. One important contribution of this paper is to introduce a model selection approach to DE and DV gene identification, which is most commonly tackled by null hypothesis testing approaches. We show that our approach is robust in analyzing real and simulated datasets. We believe that our approach is applicable in many ageing or time-series data analysis tasks.

Differential variability analysis of gene expression and its application to human diseases.

MOTIVATION: Current microarray analyses focus on identifying sets of genes that are differentially expressed (DE) or differentially coexpressed (DC) in different biological states (e.g. diseased versus non-diseased). We observed that in many human diseases, some genes have a significant increase or decrease in expression variability (variance). As these observed changes in expression variability may be caused by alteration of the underlying expression dynamics, such differential variability (DV) patterns are also biologically interesting. RESULTS: Here we propose a novel analysis for changes in gene expression variability between groups of samples, which we call differential variability analysis. We introduce the concept of differential variability (DV), and present a simple procedure for identifying DV genes from microarray data. Our procedure is evaluated with simulated and real microarray datasets. The effect of data preprocessing methods on identification of DV gene is investigated. The biological significance of DV analysis is demonstrated with four human disease datasets. The relationships among DV, DE and DC genes are investigated. The results suggest that changes in expression variability are associated with changes in coexpression pattern, which imply that DV is not merely stochastic noise, but informative signal. AVAILABILITY: The R source code for differential variability analysis is available from the contact authors upon request.

The effect of resveratrol on a cell model of human aging.

The natural polyphenol resveratrol stimulates sirtuins and extends lifespan. Here resveratrol inhibited expression of replicative senescence marker INK4a in human dermal fibroblasts, and 47 of 19,000 genes from microarray experiments were differentially expressed. These included genes for growth, cell division, cell signaling, apoptosis, and transcription. Genes involved in Ras and ubiquitin pathways, Ras-GRF1, RAC3, and UBE2D3, were downregulated. The changes suggest resveratrol might alter sirtuin-regulated downstream pathways, rather than sirtuin activity. Serum deprivation and high confluency caused nuclear translocation of the SIRT1-regulated transcription factor FOXO3a. Our data indicate resveratrol's actions might cause FOXO recruitment to the nucleus.

Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation.

G protein-coupled receptors are the principal mediators of the sweet, umami, bitter, and fat taste qualities in mammals. Intriguingly, the taste receptors are also expressed outside of the oral cavity, including in the gut, airways, brain, and heart, where they have additional functions and contribute to disease. However, there is little known about the mechanisms governing the transcriptional regulation of taste receptor genes. Following our recent delineation of taste receptors in the heart, we investigated the genomic loci encoding for taste receptors to gain insight into the regulatory mechanisms that drive their expression in the heart. Gene expression analyses of healthy and diseased human and mouse hearts showed coordinated expression for a subset of chromosomally clustered taste receptors. This chromosomal clustering mirrored the cardiac expression profile, suggesting that a common gene regulatory block may control the taste receptor locus. We identified unique domains with strong regulatory potential in the vicinity of taste receptor genes. We also performed de novo motif enrichment in the proximal promoter regions and found several overrepresented DNA motifs in cardiac taste receptor gene promoters corresponding to ubiquitous and cardiac-specific transcription factor binding sites. Thus, combining cardiac gene expression data with bioinformatic analyses, this study has provided insights into the noncoding regulatory landscape for taste GPCRs. These findings also have broader relevance for the study of taste GPCRs outside of the classical gustatory system, where understanding the mechanisms controlling the expression of these receptors may have implications for future therapeutic development.

Withdrawal of anti-epileptic medications during video EEG monitoring does not alter ECG parameters or HRV.

PURPOSE: To assess if anti-epileptic drug (AED) withdrawal/cessation results in changes in ECG parameters and/or measures of heart rate variability (HRV), in patients having VEEG monitoring, that might affect susceptibility to sudden death in epilepsy. METHODS: In this study, we included 36 patients with medically refractory epilepsy undergoing continuous video-EEG-ECG monitoring in hospital for pre-surgical assessment. We recorded and analysed multiple 10-min epochs of 2-lead ECG during periods when the subjects were awake and in REM and non-REM sleep, both on admission, and after the subjects had been partially or completely weaned from their AEDs. We compared ECG parameters and measures of HRV from these recorded epochs before and after AED reduction/cessation, with each patient acting as their own comparator. Epochs measured during awake, REM, and non-REM periods were analysed separately. In addition, we analysed a subgroup of patients who had been withdrawn from Na+-channel blocking medications specifically, to analyse the effect of this particular class of AEDs in isolation. KEY FINDINGS: Upon AED withdrawal, we observed a small increase in heart rate and shortening of the QT interval, when subjects were awake, but no other changes in ECG parameters were detected, nor did we find changes in any measure of HRV. In addition, no significant changes were found during sleep. Similar results were found in the analysis of the subgroup of patients withdrawn from Na+-channel blocking AEDs. SIGNIFICANCE: Our study does not support a prominent role for AEDs, and withdrawal/cessation of AEDs, in deranging cardiac physiology during video EEG monitoring in medically refractory epilepsy patients undergoing video EEG monitoring.