A Proof of Concept of the Usefulness of a TDM-Guided Strategy for Optimizing Pharmacokinetic/Pharmacodynamic Target of Continuous Infusion Ampicillin-Based Regimens in a Case Series of Patients with Enterococcal Bloodstream Infections and/or Endocarditis

(1) Objective: To describe the usefulness of a real-time therapeutic drug monitoring (TDM)-based strategy for optimizing pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ampicillin-based regimens in a case series of patients affected by suspected or documented enterococcal bloodstream infections (BSIs) and/or infective endocarditis (IE). (2) Methods: Patients treated with CI ampicillin-based regimens for documented or suspected enterococcal BSI/IE who underwent real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) between June 2021 and May 2022 were retrospectively assessed. Ampicillin concentrations were determined at steady state, and the free fraction (fC(ss)) was calculated according to a plasma protein binding of 20%. The fC(ss)/MIC ratio was selected as the PD parameter for ampicillin efficacy and was defined as optimal for values between 4 and 8. The requirement for TDM-guided ampicillin dosing adjustments was assessed. (3) Results: Data for 12 patients with documented (n = 10) or suspected (n = 2) enterococcal infections (7 with BSIs and 5 with IE) were retrieved. The ampicillin PK/PD target was optimal over time in all of the 10 documented infections. None of the enterococcal BSIs persisted. Following the first real-time TDM-based ECPA, ampicillin dosage was decreased by >50% in 11 out of 12 patients (91.7%). (4) Conclusions: CI may be helpful in attaining aggressive ampicillin PK/PD targets in patients affected by enterococcal BSIs and/or IE. Administration of CI ampicillin after loading coupled with real-time TDM-based ECPA could be a valuable strategy for managing enterococcal infections

Human Polyomaviruses in the Cerebrospinal Fluid of Neurological Patients.

BACKGROUND: Central nervous system (CNS) infections by human polyomaviruses (HPyVs), with the exception of JC (JCPyV), have been poorly studied. METHODS: In total, 234 cerebrospinal fluid (CSF) samples were collected from patients affected with neurological disorders. DNA was isolated and subjected to quantitative real-time PCR (Q-PCR) for the detection of six HPyVs: JCPyV, BKPyV, Merkel cell PyV (MCPyV), HPyV6, HPyV7, and HPyV9. Where possible, the molecular characterization of the viral strains was carried out by nested PCR and automated sequencing. RESULTS: JCPyV was detected in 3/234 (1.3%), BKPyV in 15/234 (6.4%), MCPyV in 22/234 (9.4%), and HPyV6 in 1/234 (0.4%) CSF samples. JCPyV was detected at the highest (p < 0.05) mean load (3.7 7 107 copies/mL), followed by BKPyV (1.9 7 106 copies/mL), MCPyV (1.9 7 105 copies/mL), and HPyV6 (3.3 7 104 copies/mL). The noncoding control regions (NCCRs) of the sequenced viral strains were rearranged. CONCLUSIONS: HPyVs other than JCPyV were found in the CSF of patients affected with different neurological diseases, probably as bystanders, rather than etiological agents of the disease. However, the fact that they can be latent in the CNS should be considered, especially in immunosuppressed patients

In-Network Outlier Detection in Wireless Sensor Networks

To address the problem of unsupervised outlier detection in wireless sensor networks, we develop an approach that (1) is flexible with respect to the outlier definition, (2) computes the result in-network to reduce both bandwidth and energy usage,(3) only uses single hop communication thus permitting very simple node failure detection and message reliability assurance mechanisms (e.g., carrier-sense), and (4) seamlessly accommodates dynamic updates to data. We examine performance using simulation with real sensor data streams. Our results demonstrate that our approach is accurate and imposes a reasonable communication load and level of power consumption.Comment: Extended version of a paper appearing in the Int'l Conference on Distributed Computing Systems 200

Effects of descending positive end-expiratory pressure on lung mechanics and aeration in healthy anaesthetized piglets

INTRODUCTION: Atelectasis and distal airway closure are common clinical entities of general anaesthesia. These two phenomena are expected to reduce the ventilation of dependent lung regions and represent major causes of arterial oxygenation impairment in anaesthetic conditions. The behaviour of the elastance of the respiratory system (E(rs)), as well as the lung aeration assessed by computed tomography (CT) scan, was evaluated during a descendent positive end-expiratory pressure (PEEP) titration. This work sought to evaluate the potential usefulness of E(rs )monitoring to set the PEEP in order to prevent tidal recruitment and hyperinflation of healthy lungs under general anaesthesia. METHODS: PEEP titration (from 16 to 0 cmH(2)O, tidal volume of 8 ml/kg) was performed, and at each PEEP, CT scans were obtained during end-expiratory and end-inspiratory pauses in six healthy, anaesthetized and paralyzed piglets. The distribution of lung aeration was determined and the tidal re-aeration was calculated as the difference between end-expiratory and end-inspiratory poorly aerated and normally aerated areas. Similarly, tidal hyperinflation was obtained as the difference between end-inspiratory and end-expiratory hyperinflated areas. E(rs )was estimated from the equation of motion of the respiratory system during all PEEP titration with the least-squares method. RESULTS: Hyperinflated areas decreased from PEEP 16 to 0 cmH(2)O (ranges decreased from 24–62% to 1–7% at end-expiratory pauses and from 44–73% to 4–17% at end-inspiratory pauses) whereas normally aerated areas increased (from 30–66% to 72–83% at end-expiratory pauses and from 19–48% to 73–77% at end-inspiratory pauses). From 16 to 8 cmH(2)O, E(rs )decreased with a corresponding reduction in tidal hyperinflation. A flat minimum of E(rs )was observed from 8 to 4 cmH(2)O. For PEEP below 4 cmH(2)O, E(rs )increased in association with a rise in tidal re-aeration and a flat maximum of the normally aerated areas. CONCLUSION: In healthy piglets under a descending PEEP protocol, the PEEP at minimum E(rs )presented a compromise between maximizing normally aerated areas and minimizing tidal re-aeration and hyperinflation. High levels of PEEP, greater than 8 cmH(2)O, reduced tidal re-aeration but increased hyperinflation with a concomitant decrease in normally aerated areas

Apoptosis rate and transcriptional response of pancreatic islets exposed to the PPAR gamma agonist Pioglitazone

To explore the molecular pathways underlying thiazolidinediones effects on pancreatic islets in conditions mimicking normo- and hyperglycemia, apoptosis rate and transcriptional response to Pioglitazone at both physiological and supraphysiological glucose concentrations were evaluated. Adult rat islets were cultured at physiological (5.6 mM) and supraphysiological (23 mM) glucose concentrations in presence of 10 μM Pioglitazone or vehicle. RNA expression profiling was evaluated with the PancChip 13k cDNA microarray after 24-h, and expression results for some selected genes were validated by qRT-PCR. The effects of Pioglitazone were investigated regarding apoptosis rate after 24-, 48- and 72-h. At 5.6 mM glucose, 101 genes were modulated by Pioglitazone, while 1,235 genes were affected at 23 mM glucose. Gene networks related to lipid metabolism were identified as altered by Pioglitazone at both glucose concentrations. At 23 mM glucose, cell cycle and cell death pathways were significantly regulated as well. At 5.6 mM glucose, Pioglitazone elicited a transient reduction in islets apoptosis rate while at 23 mM, Bcl2 expression was reduced and apoptosis rate was increased by Pioglitazone. Our data demonstrate that the effect of Pioglitazone on gene expression profile and apoptosis rate depends on the glucose concentration. The modulation of genes related to cell death and the increased apoptosis rate observed at supraphysiological glucose concentration raise concerns about Pioglitazone’s direct effects in conditions of hyperglycemia and reinforce the necessity of additional studies designed to evaluate TZDs effects on the preservation of β-cell function in situations where glucotoxicity might be more relevant than lipotoxicity.This work was supported by grants from NIDDK (UO1 DK 56947; P30 DK 19525) and from FAPESP (04/018165, 04/014670 and 04/107974). The authors are grateful to Takeda Chemicals Industries (Japan) for supplying pioglitazone hydrochloride pure substance.This work was supported by grants from NIDDK (UO1 DK 56947; P30 DK 19525) and from FAPESP (04/01816-5, 04/01467-0 and 04/10797-4). The authors are grateful to Takeda Chemicals Industries (Japan) for supplying pioglitazone hydrochloride pure substance

Harmonization and standardization of data for a pan-European cohort on SARS- CoV-2 pandemic

The European project ORCHESTRA intends to create a new pan-European cohort to rapidly advance the knowledge of the effects and treatment of COVID-19. Establishing processes that facilitate the merging of heterogeneous clusters of retrospective data was an essential challenge. In addition, data from new ORCHESTRA prospective studies have to be compatible with earlier collected information to be efficiently combined. In this article, we describe how we utilized and contributed to existing standard terminologies to create consistent semantic representation of over 2500 COVID-19-related variables taken from three ORCHESTRA studies. The goal is to enable the semantic interoperability of data within the existing project studies and to create a common basis of standardized elements available for the design of new COVID-19 studies. We also identified 743 variables that were commonly used in two of the three prospective ORCHESTRA studies and can therefore be directly combined for analysis purposes. Additionally, we actively contributed to global interoperability by submitting new concept requests to the terminology Standards Development Organizations

Non-fermentative gram-negative bloodstream infection in northern Italy: a multicenter cohort study

Background: The management of non-fermentative gram-negative bloodstream infection (NFGN-BSI) offers numerous challenges. In this study the aim is to analyse a large cohort of patients with NFGN-BSI recruited in the northern Italy to describe epidemiology, etiological and susceptibility pattern, therapeutic management and outcome. Methods: Multicentre retrospective cohort study of patients hospitalised at three large teaching hospitals in northern Italy in a fourth year period. Results: 355 BSI episodes were analyzed, due to P. aeruginosa (72.7%), A. baumannii (16.6%), and Stenotrophomonas maltophilia (10.7%). Overall, 21.4% of isolates were defined as DTR, highest rate among A. baumannii (64.4%). All-cause 30-day mortality rate was 17.5%. Rates of XDR or DTR A. baumannii isolation were significantly higher in non-surviving patients. Independent risk factors for 30-day mortality were: age (HR 1.03, 95%CI 1.00–1.04, p = 0.003), septic shock (HR 2.84, 95%CI 1.67–4.82, p &lt; 0.001) and BSI due to Acinetobacter baumannii (HR 2.23, 95%CI 1.27–3.94, p = 0.005). Conclusion: The overall prevalence of DTR was high in the NFGN BSI cohort analyzied, mainly among Acinetobacter baumannii episodes (64.4%). Acinetobacter baumannii is showed to be an independent predictor of mortality. These evidences marked the urgent need of new therapeutic options against this pathogen. Trial registration number: 79/2017/O/OssN. Approved: March14th, 2017

Non-fermentative gram-negative bloodstream infection in northern Italy: a multicenter cohort study

BACKGROUND: The management of non-fermentative gram-negative bloodstream infection (NFGN-BSI) offers numerous challenges. In this study the aim is to analyse a large cohort of patients with NFGN-BSI recruited in the northern Italy to describe epidemiology, etiological and susceptibility pattern, therapeutic management and outcome. METHODS: Multicentre retrospective cohort study of patients hospitalised at three large teaching hospitals in northern Italy in a fourth year period. RESULTS: 355 BSI episodes were analyzed, due to P. aeruginosa (72.7%), A. baumannii (16.6%), and Stenotrophomonas maltophilia (10.7%). Overall, 21.4% of isolates were defined as DTR, highest rate among A. baumannii (64.4%). All-cause 30-day mortality rate was 17.5%. Rates of XDR or DTR A. baumannii isolation were significantly higher in non-surviving patients. Independent risk factors for 30-day mortality were: age (HR 1.03, 95%CI 1.00–1.04, p = 0.003), septic shock (HR 2.84, 95%CI 1.67–4.82, p < 0.001) and BSI due to Acinetobacter baumannii (HR 2.23, 95%CI 1.27–3.94, p = 0.005). CONCLUSION: The overall prevalence of DTR was high in the NFGN BSI cohort analyzied, mainly among Acinetobacter baumannii episodes (64.4%). Acinetobacter baumannii is showed to be an independent predictor of mortality. These evidences marked the urgent need of new therapeutic options against this pathogen. Trial registration number: 79/2017/O/OssN. Approved: March14th, 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-021-06496-8