Development of Modernized Acinetobacter baumannii Susceptibility Test Interpretive Criteria for Recommended Antimicrobial Agents Using Pharmacometric Approaches.

Acinetobacter baumannii-Acinetobacter calcoaceticus complex (referred to herein as A. baumannii) treatment guidelines contain numerous older antimicrobial agents with susceptibility test interpretive criteria (STIC, also known as susceptibility breakpoints) set using only epidemiological data. We utilized a combination of in vitro surveillance data, preclinical murine thigh and lung infection models, population pharmacokinetics, simulation, and pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses to evaluate A. baumannii STIC for four commonly recommended antimicrobials from different classes (amikacin, ceftazidime, ciprofloxacin, and minocycline). Antimicrobial in vitro surveillance data were based on 1,647 clinical A. baumannii isolates obtained from 109 centers in the United States and Europe. Among these isolates, 5 were selected for evaluation in murine infection models based on fitness and MIC variability. PK and dose-ranging studies were conducted using neutropenic murine thigh and lung infection models The MIC ranges for the 5 isolates evaluated were as follows: amikacin, 2 to 32 µg/mL; ceftazidime, 4 to 16 µg/mL; ciprofloxacin, 0.12 to 2 µg/mL; minocycline, 0.25 to 4 µg/mL. All organisms grew ≥1.5 log10 CFU in both models in untreated controls. Plasma and epithelial lining fluid (ELF) pharmacokinetics for all drugs were determined in mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. For each isolate, 5 dose levels of each drug were tested individually in the thigh and lung infection model. The inoculum ranged from 7.9 to 8.4 and 6.8 to 7.7 log10 CFU/mL for the lung and thigh models, respectively. PK/PD targets associated with net bacterial stasis and 1- and 2-log10 CFU reductions from baseline were identified for each organism/infection model using Hill-type models. Population pharmacokinetic models for each agent were identified from the literature. Using demographic variables for simulated patients with hospital-acquired or ventilator-associated bacterial pneumonia or urinary tract infections (including acute pyelonephritis) who were administered maximal dosing regimens of each agent, estimates of protein binding, and ELF penetration ratios based on data from the literature, free-drug plasma and total-drug concentration-time profiles were generated, and PK/PD indices by MIC were calculated. Percent probabilities of attaining median and randomly assigned PK/PD targets associated with the above-described endpoints were determined. Recommended susceptible breakpoints for each agent were those representing the highest MIC at which the percent probabilities of achieving PK/PD targets associated with a 1-log10 CFU reduction from baseline approached or were ≥90%. The following susceptible breakpoints for A. baumannii were identified: amikacin, ≤8 µg/mL for pneumonia; ceftazidime, ≤32 and ≤8 µg/mL for pneumonia; ciprofloxacin, ≤1 µg/mL; and minocycline, ≤0.5/≤1 µg/mL which correspond to the standard and high minocycline dosing regimens of 200 mg per day and 200 mg every 12 h, respectively. Implementation of appropriate STIC will help clinicians optimally use the above-described agents and improve the likelihood of successful patient outcomes.

Evaluation of the Impact of Comorbidities on Omadacycline Pharmacokinetics.

Omadacycline is approved in the United States for the treatment of patients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections. Analyses were undertaken to evaluate pharmacokinetic differences among subjects or patients stratified by comorbidities. Differences in clearance by smoking status, history of diabetes mellitus, chronic lung disease, hypertension, heart failure, or coronary artery disease were evaluated using a Welch two-sample t test. Smoking was the only significant comorbidity after correction for sex, with a clinically insignificant difference of 13%. Omadacycline dose adjustments based on these comorbidities do not appear to be warranted.

Effect of Early High-Flow Nasal Oxygen vs Standard Oxygen Therapy on Length of Hospital Stay in Hospitalized Children With Acute Hypoxemic Respiratory Failure: The PARIS-2 Randomized Clinical Trial.

Importance: Nasal high-flow oxygen therapy in infants with bronchiolitis and hypoxia has been shown to reduce the requirement to escalate care. The efficacy of high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure without bronchiolitis is unknown. Objective: To determine the effect of early high-flow oxygen therapy vs standard oxygen therapy in children with acute hypoxemic respiratory failure. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted at 14 metropolitan and tertiary hospitals in Australia and New Zealand, including 1567 children aged 1 to 4 years (randomized between December 18, 2017, and March 18, 2020) requiring hospital admission for acute hypoxemic respiratory failure. The last participant follow-up was completed on March 22, 2020. Interventions: Enrolled children were randomly allocated 1:1 to high-flow oxygen therapy (n = 753) or standard oxygen therapy (n = 764). The type of oxygen therapy could not be masked, but the investigators remained blinded until the outcome data were locked. Main Outcomes and Measures: The primary outcome was length of hospital stay with the hypothesis that high-flow oxygen therapy reduces length of stay. There were 9 secondary outcomes, including length of oxygen therapy and admission to the intensive care unit. Children were analyzed according to their randomization group. Results: Of the 1567 children who were randomized, 1517 (97%) were included in the primary analysis (median age, 1.9 years [IQR, 1.4-3.0 years]; 732 [46.7%] were female) and all children completed the trial. The length of hospital stay was significantly longer in the high-flow oxygen group with a median of 1.77 days (IQR, 1.03-2.80 days) vs 1.50 days (IQR, 0.85-2.44 days) in the standard oxygen group (adjusted hazard ratio, 0.83 [95% CI, 0.75-0.92]; P < .001). Of the 9 prespecified secondary outcomes, 4 showed no significant difference. The median length of oxygen therapy was 1.07 days (IQR, 0.50-2.06 days) in the high-flow oxygen group vs 0.75 days (IQR, 0.35-1.61 days) in the standard oxygen therapy group (adjusted hazard ratio, 0.78 [95% CI, 0.70-0.86]). In the high-flow oxygen group, there were 94 admissions (12.5%) to the intensive care unit compared with 53 admissions (6.9%) in the standard oxygen group (adjusted odds ratio, 1.93 [95% CI, 1.35-2.75]). There was only 1 death and it occurred in the high-flow oxygen group. Conclusions and Relevance: Nasal high-flow oxygen used as the initial primary therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not significantly reduce the length of hospital stay compared with standard oxygen therapy. Trial Registration: anzctr.org.au Identifier: ACTRN12618000210279.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.

Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.

Caring for the whole person: transgender-competent HIV pre-exposure prophylaxis as part of integrated primary healthcare services in Vietnam.

INTRODUCTION: Although HIV prevalence among transgender women who have sex with men in Vietnam is high (16-18%), uptake of pre-exposure prophylaxis (PrEP) is low compared to other populations. When PrEP was initiated in 2017, gender-affirming healthcare was largely unavailable. Lack of access to competent, stigma-free healthcare is a well-documented barrier to transgender women's uptake of PrEP and primary healthcare (PHC). We aimed to demonstrate the utility of a PrEP quality improvement intervention in pinpointing and addressing barriers to PrEP use among transgender women in Vietnam. METHODS: We applied a real-world participatory continuous quality improvement (CQI) and Plan-Do-Study-Act (PDSA) methodology to ascertain barriers to PrEP uptake among transgender women and determine priority actions for quality improvement. A CQI team representing transgender women leaders, key population (KP)-clinic staff, public-sector HIV managers and project staff applied PDSA to test solutions to identified barriers that addressed the primary quality improvement outcome of the monthly change in PrEP uptake among transgender women and secondary outcomes, including month-3 PrEP continuation, the impact of offering PHC on PrEP uptake and unmet PrEP need. We utilized routine programmatic data and a descriptive cross-sectional study enrolling 124 transgender women to measure these outcomes from October 2018 to September 2021. RESULTS: Five key barriers to PrEP uptake among transgender women were identified and corresponding solutions were put in place: (1) offering gender-affirming care training to KP-clinics and community-based organizations; (2) integrating gender-affirming services into 10 KP-clinics; (3) offering PHC through five one-stop shop (OSS) clinics; (4) implementing a campaign addressing concerns related to hormone use and PrEP interactions; and (5) developing national HIV and transgender healthcare guidelines. New PrEP enrolment and month-3 PrEP continuation increased significantly among transgender women. Of 235 transgender women who initially sought healthcare other than PrEP at OSS clinics, 26.4% subsequently enrolled in PrEP. About one-third of transgender women reported unmet PrEP need, while two-thirds indicated an interest in long-acting cabotegravir. CONCLUSIONS: Offering gender-competent, integrated PHC can increase PrEP enrolment and continuation, and can be an entry-point for PrEP among those seeking care within PHC clinics. More work is needed to expand access to transgender women-led and -competent healthcare in Vietnam.

Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Noninfected Subjects and Infected Patients.

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties.

Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.

Nasal High Flow in Room Air for Hypoxemic Bronchiolitis Infants.

Background: Bronchiolitis is the most common reason for hospital admission in infants, with one third requiring oxygen therapy due to hypoxemia. It is unknown what proportion of hypoxemic infants with bronchiolitis can be managed with nasal high-flow in room air and their resulting outcomes. Objectives and Settings: To assess the effect of nasal high-flow in room air in a subgroup of infants with bronchiolitis allocated to high-flow therapy in a recent multicenter randomized controlled trial. Patients and Interventions: Infants allocated to the high-flow arm of the trial were initially treated with room air high-flow if saturations were ≥85%. Subsequently, if oxygen saturations did not increase to ≥92%, oxygen was added and FiO2 was titrated to increase the oxygen saturations. In this planned sub-study, infants treated during their entire hospital stay with high-flow room air only were compared to infants receiving either standard-oxygen or high-flow with oxygen. Baseline characteristics, hospital length of stay and length of oxygen therapy were compared. Findings: In the per protocol analysis 64 (10%) of 630 infants commenced on high-flow room air remained in room air only during the entire stay in hospital. These infants on high-flow room air were on average older and presented with moderate hypoxemia at presentation to hospital. Their length of respiratory support and length of stay was also significantly shorter. No pre-enrolment factors could be identified in a multivariable analysis. Conclusions: In a small sub-group of hypoxemic infants with bronchiolitis hypoxemia can be reversed with the application of high-flow in room air only. Trial registration: ACTRN12615001305516.

From conventional to disruptive: upturning the HIV testing status quo among men who have sex with men in Vietnam.

INTRODUCTION: HIV prevalence among men who have sex with men (MSM) in Vietnam is increasing, while annual HIV testing uptake has remained consistently low, posing a significant challenge to reaching the 90-90-90 goals. Barriers to MSM seeking HIV testing include concerns regarding confidentiality and lack of convenient testing options. Two new HIV testing strategies-HIV lay provider and HIV self-testing (HIVST)-were piloted alongside intensive social media outreach to increase access to and uptake of HIV testing among MSM not actively engaged in services. METHODS: We measured the proportion of first-time MSM HIV testers opting for HIV lay or self-testing, and factors that were associated with first-time testing, as part of a larger HIV lay and self-testing study among key populations in Vietnam. We also assessed MSM satisfaction with HIV lay or self-testing, and testing location and provider preferences. Finally, we calculated linkage to care cascade among MSM that were diagnosed and enrolled in anti-retroviral therapy (ART) services. RESULTS: Among MSM that sought HIV lay and self-testing, 57.9% (n = 320) and 51.3% (n = 412) were first-time testers respectively. In the final adjusted models, the odds of being a first-time tester and opting for HIV lay testing were higher among MSM who were young, had lower levels of income and had never exchanged sex for money; for HIVST, the odds of being a first-time HIV tester were higher among MSM that had attained lower levels of education. HIV lay and self-testing resulted in higher detection of new HIV cases (6.8%) compared to conventional HIV testing among key populations (estimated at 1.6% in 2016), while MSM linked to testing through social media interventions presented with even higher HIV-positivity (11%). Combined, 1655 HIV cases were diagnosed and more than 90% were registered for ART services. CONCLUSIONS: Our findings suggest that MSM-delivered HIV testing and self-testing, promoted through online or face-to-face interactions, offer important additions to MSM HIV testing services in Vietnam, and could significantly contribute to epidemic control by increasing HIV testing among harder-to-reach and higher-risk MSM, effectively enrolling them in ART, and reducing onward transmission.

D3NER: biomedical named entity recognition using CRF-biLSTM improved with fine-tuned embeddings of various linguistic information.

Motivation: Recognition of biomedical named entities in the textual literature is a highly challenging research topic with great interest, playing as the prerequisite for extracting huge amount of high-valued biomedical knowledge deposited in unstructured text and transforming them into well-structured formats. Long Short-Term Memory (LSTM) networks have recently been employed in various biomedical named entity recognition (NER) models with great success. They, however, often did not take advantages of all useful linguistic information and still have many aspects to be further improved for better performance. Results: We propose D3NER, a novel biomedical named entity recognition (NER) model using conditional random fields and bidirectional long short-term memory improved with fine-tuned embeddings of various linguistic information. D3NER is thoroughly compared with seven very recent state-of-the-art NER models, of which two are even joint models with named entity normalization (NEN), which was proven to bring performance improvements to NER. Experimental results on benchmark datasets, i.e. the BioCreative V Chemical Disease Relation (BC5 CDR), the NCBI Disease and the FSU-PRGE gene/protein corpus, demonstrate the out-performance and stability of D3NER over all compared models for chemical, gene/protein NER and over all models (without NEN jointed, as D3NER) for disease NER, in almost all cases. On the BC5 CDR corpus, D3NER achieves F1 of 93.14 and 84.68% for the chemical and disease NER, respectively; while on the NCBI Disease corpus, its F1 for the disease NER is 84.41%. Its F1 for the gene/protein NER on FSU-PRGE is 87.62%. Availability and implementation: Data and source code are available at: https://github.com/aidantee/D3NER. Supplementary information: Supplementary data are available at Bioinformatics online.

Increasing Access to Hepatitis C Virus Medications: A Program Model Using Patient Navigators and Specialty Pharmacy to Obtain Prior Authorization Approval.

BACKGROUND: Obtaining prior authorization (PA) approval for the new direct-acting antiviral (DAA) hepatitis C medications is time consuming and requires specific expertise. Our primary care-based program treats hepatitis C virus (HCV)-infected patients at an urban academic medical center and employs patient navigators trained in the PA process who collaborate with a nurse and specialty pharmacy to manage the PA process. OBJECTIVE: To demonstrate the rate of PA approvals for our programmatic model and determine potential predictors of PA approval. METHODS: We conducted a review of program databases and medical records of patients for whom DAA hepatitis C medications were ordered between November 1, 2014, and October 31, 2015 (n = 197). We first evaluated patient characteristics associated with the number of steps to approval. Then we used a multivariable ordinal regression to determine independent predictors of fewer steps to approval. Using Kaplan-Meier methods, we assessed patient characteristics associated with approval time and then fit a multivariable Cox regression model to determine independent predictors of time to approval. RESULTS: Of the 197 patients, 69% (n = 136) had Medicaid; 12% (n = 24) had Medicare; 10% (n = 19) had both Medicaid and Medicare; 5% (n = 10) had private insurance; and 4% (n = 8) were uninsured. Ninety-three percent of the patients were eventually approved for HCV treatment. The steps in the PA cascade were approval on first submission (37%; mean days = 30.7; SD = 29.9); approval after internal appeal (45%; mean days = 66.8; SD = 70.5); approval after external appeal (11%; mean days = 124.7; SD = 60.2); and no approval obtained (7%). Unadjusted factors found to have a P value < 0.200 in relation to fewer steps in the PA cascade were older age, female gender, non-Medicaid insurance, comorbid hypertension, comorbid diabetes, being domiciled, and being nongenotype 2. After adjustment, non-Medicaid insurance and nongenotype 2 remained significant. In survival analysis, non-Medicaid insurance and mid-range fibrosis were associated with fewer days to PA approval. CONCLUSIONS: Our program obtained 93% of PA approvals for hepatitis C medications. Patient navigators collaborating with a nurse and specialty pharmacy as a program may improve the PA approval process, although further research with a control group is necessary. DISCLOSURES: The Respectful & Equitable Access to Comprehensive Healthcare (REACH) program receives funding from the Robin Hood Foundation and the New York State Department of Health AIDS Institute. Weiss receives grant support from Gilead Sciences and has served as a consultant for AbbVie and Gilead Sciences. Vu reports speaker fees from Peer View Institute. All other authors report no conflict of interest. Study design and concept were contributed by Chasan, Sigel, Vu, and Weiss. Riazi, Ciprian, Giardina, and Gibbs collected the data, which were interpreted by Toribio, Amory, Chasan, and Sigel. The manuscript was written by Vu and Weiss and revised by Parrella, Cambe, Camacho, and Vu. Research from this study was presented as an abstract poster on November 14, 2016, at the AASLD Liver Meeting in Boston, Massachusetts.

Hepatitis C Core Antigen Testing for Diagnosis of Hepatitis C Virus Infection: A Systematic Review and Meta-analysis.

BACKGROUND: Diagnosis of chronic hepatitis C virus (HCV) infection requires both a positive HCV antibody screen and confirmatory nucleic acid testing (NAT). Testing for hepatitis C virus core antigen (HCVcAg) is a potential alternative to NAT. PURPOSE: To evaluate the accuracy of diagnosis of active HCV infection among adults and children for 5 HCVcAg tests compared with NAT. DATA SOURCES: EMBASE, PubMed, Web of Science, Scopus, and Cochrane Database of Systematic Reviews from 1990 through 31 March 2016. STUDY SELECTION: Case-control, cross-sectional, cohort, or randomized trials that compared any of 5 HCVcAg tests with an NAT reference standard. DATA EXTRACTION: 2 independent reviewers extracted data and assessed quality using an adapted QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool. DATA SYNTHESIS: 44 studies evaluated 5 index tests. Studies for the Abbott ARCHITECT HCV Ag assay had the highest quality, whereas those for the Ortho HCV Ag enzyme-linked immunosorbent assay (ELISA) had the lowest quality. From bivariate analyses, the sensitivity and specificity of the assays were as follows: Abbott ARCHITECT, 93.4% (95% CI, 90.1% to 96.4%) and 98.8% (CI, 97.4% to 99.5%); Ortho ELISA, 93.2% (CI, 81.6% to 97.7%) and 99.2% (CI, 87.9% to 100%); and Hunan Jynda Bioengineering Group HCV Ag ELISA, 59.5% (CI, 46.0% to 71.7%) and 82.9% (CI, 58.6% to 94.3%). Insufficient data were available for a meta-analysis about the Fujirebio Lumipulse Ortho HCV Ag and Eiken Lumispot HCV Ag assays. In 3 quantitative studies using Abbott ARCHITECT, HCVcAg correlated closely with HCV RNA levels greater than 3000 IU/mL. LIMITATIONS: Insufficient data were available on covariates, such as HIV or hepatitis B virus status, for subgroup analyses. Few studies reported genotypes of isolates, and data for genotypes 4, 5, and 6 were scant. Most studies were conducted in high-resource settings and reference laboratories. CONCLUSION: The HCVcAg assays with signal amplification have high sensitivity, high specificity, and good correlation with HCV RNA levels greater than 3000 IU/mL and have the potential to replace NAT in settings with high HCV prevalence. PRIMARY FUNDING SOURCE: National Institutes of Health.

Pteridine-2,4-diamine derivatives as radical scavengers and inhibitors of lipoxygenase that can possess anti-inflammatory properties.

BACKGROUND: Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species. RESULTS: A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%). CONCLUSION: The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties.

The effect of high flow nasal cannula therapy on the work of breathing in infants with bronchiolitis.

The main physiological impact of high flow nasal cannula (HFNC) therapy is presumed to be a decrease in work of breathing (WOB). To assess this, diaphragmatic electrical activity and esophageal pressure changes were measured off then on HFNC delivered at 2 L/kg/min, in 14 infants with bronchiolitis and 14 cardiac infants. Electrical activity of the diaphragm (Edi) was measured using an Edi catheter with calculations of signal peak (EdiMAX ) and amplitude (EdiAMPL ). Pressure-rate and pressure-time products (PRP, PTP) were calculated from analyses of esophageal pressure. Changes in end-expiratory lung volume were measured using respiratory inductance plethysmography (RIPEEL ). The EdiMAX and EdiAMPL were significantly higher in infants with bronchiolitis than in cardiac infants (P < 0.05). Within the bronchiolitis group, both were significantly reduced between HFNC states from 27.9 µV [20.4, 35.4] to 21.0 µV [14.8, 27.2] and from 25.1 µV [18.0, 32.2] to 19.2 µV [13.3, 25.1], respectively (mean, 95% CI, P < 0.05). A less prominent offload of the diaphragm was observed in cardiac infants (P < 0.05). WOB decreased in both groups with a significant reduction of PRP and PTP (P < 0.05). RIPEEL increased significantly in bronchiolitis only (P < 0.05). HFNC offloads the diaphragm and reduces the WOB in bronchiolitis. A similar effect was demonstrated in cardiac infants, a group without signs of airway-obstruction.

Physiologic effect of high-flow nasal cannula in infants with bronchiolitis.

OBJECTIVE: To assess the effect of delivering high-flow nasal cannula flow on end-expiratory lung volume, continuous distending pressure, and regional ventilation distribution in infants less than 12 months old with bronchiolitis. DESIGN: Prospective observational clinical study. SETTING: Nineteen bed medical and surgical PICU. PATIENTS: Thirteen infants with bronchiolitis on high-flow nasal therapy. INTERVENTIONS: The study infants were measured on a flow rate applied at 2 and 8 L/min through the high-flow nasal cannula system. MEASUREMENTS AND RESULTS: Ventilation distribution was measured with regional electrical impedance amplitudes and end-expiratory lung volume using electrical impedance tomography. Changes in continuous distending pressure were measured from the esophagus via the nasogastric tube. Physiological variables were also recorded. High-flow nasal cannula delivered at 8 L/min resulted in significant increases in global and anterior end-expiratory lung volume (p < 0.01) and improvements in the physiological variables of respiratory rate, SpO2, and FIO2 when compared with flows of 2 L/min. CONCLUSION: In infants with bronchiolitis, high-flow nasal cannula oxygen/air delivered at 8 L/min resulted in increases in end-expiratory lung volume and improved respiratory rate, FIO2, and SpO2.

Ventilation and cardiac related impedance changes in children undergoing corrective open heart surgery.

Electrical impedance tomography (EIT) can determine ventilation and perfusion relationship. Most of the data obtained so far originates from experimental settings and in healthy subjects. The aim of this study was to demonstrate that EIT measures the perioperative changes in pulmonary blood flow after repair of a ventricular septum defect in children with haemodynamic relevant septal defects undergoing open heart surgery. In a 19 bed intensive care unit in a tertiary children's hospital ventilation and cardiac related impedance changes were measured using EIT before and after surgery in 18 spontaneously breathing patients. The EIT signals were either filtered for ventilation (ΔZV) or for cardiac (ΔZQ) related impedance changes. Impedance signals were then normalized (normΔZV, normΔZQ) for calculation of the global and regional impedance related ventilation perfusion relationship (normΔZV/normΔZQ). We observed a trend towards increased normΔZV in all lung regions, a significantly decreased normΔZQ in the global and anterior, but not the posterior lung region. The normΔZV/normΔZQ was significantly increased in the global and anterior lung region. Our study qualitatively validates our previously published modified EIT filtration technique in the clinical setting of young children with significant left-to-right shunt undergoing corrective open heart surgery, where perioperative assessment of the ventilation perfusion relation is of high clinical relevance.

A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and bromopyridazinediones.

Bromomaleimides are useful building blocks in synthesis and powerful reagents for the selective chemical modification of proteins. A mild new synthesis of these reagents is described, along with the convenient transferability of the approach to dithiomaleimides and bromopyridazinediones.

Predicting feedstock and percent composition for blends of biodiesel with conventional diesel using chemometrics and gas chromatography-mass spectrometry.

The two main goals of the analytical method described herein were to (1) use principal component analysis (PCA), hierarchical clustering (HCA) and K-nearest neighbors (KNN) to determine the feedstock source of blends of biodiesel and conventional diesel (feedstocks were two sources of soy, two strains of jatropha, and a local feedstock) and (2) use a partial least squares (PLS) model built specifically for each feedstock to determine the percent composition of the blend. The chemometric models were built using training sets composed of total ion current chromatograms from gas chromatography-quadrupole mass spectrometry (GC-qMS) using a polar column. The models were used to semi-automatically determine feedstock and blend percent composition of independent test set samples. The PLS predictions for jatropha blends had RMSEC=0.6, RMSECV=1.2, and RMSEP=1.4. The PLS predictions for soy blends had RMSEC=0.5, RMSECV=0.8, and RMSEP=1.2. The average relative error in predicted test set sample compositions was 5% for jatropha blends and 4% for soy blends.