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Multidrug-resistant (MDR) Pseudomonas aeruginosa is an important issue for physicians who take care of patients with cystic fibrosis (CF). Here, we review the latest research on how P. aeruginosa infection causes lung function to decline and how several factors contribute to the emergence of antibiotic resistance in P. aeruginosa strains and influence the course of the infection course. However, many aspects of the practical management of patients with CF infected with MDR P. aeruginosa are still to be established. Less is known about the exact role of susceptibility testing in clinical strategies for dealing with resistant infections, and there is an urgent need to find a tool to assist in choosing the best therapeutic strategy for MDR P. aeruginosa infection. One current perception is that the selection of antibiotic therapy according to antibiogram results is an important component of the decision-making process, but other patient factors, such as previous infection history and antibiotic courses, also need to be evaluated. On the basis of the known issues and the best current data on respiratory infections caused by MDR P. aeruginosa , this review provides practical suggestions to optimize the diagnostic and therapeutic management of patients with CF who are infected with these pathogens. [ABSTRACT FROM AUTHOR]

We study Moser–Trudinger type functionals in the presence of singular potentials. In particular we propose a proof of a singular Carleson–Chang type estimate by means of Onofri’s inequality for the unit disk in R 2 . Moreover we extend the analysis of Adimurthi (2004) and Csató and Roy (2015a) considering Adimurthi–Druet type functionals on compact surfaces with conical singularities and discussing the existence of extremals for such functionals. [ABSTRACT FROM AUTHOR]

In this work, an improved ultrasound technique for biometric recognition is proposed. It allows to acquire simultaneously two biometric characteristics: 3D Hand Geometry and 3D Palmprint. An open research platform is employed as ultrasound imaging system. A commercial high frequency probe is moved in the elevation direction over the region of interest by an automated scanning system based on numeric controlled pantograph. Experimental results are presented and the advantages of the proposed technique are highlighted and discussed. [ABSTRACT FROM AUTHOR]

Summary: Aim: To report an outbreak of extensively drug-resistant (XDR) Acinetobacter baumannii in the neonatal intensive care unit (NICU) of an Italian university hospital. Patient risk profiles for acquisition of A. baumannii and measures used to control the outbreak are described. Methods: Antibiotic susceptibility of strains was evaluated by microdilution. Genotyping was performed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing. Carbapenemase genes were analysed by polymerase chain reaction and DNA sequencing. A case–control study was designed to identify risk factors for acquisition of A. baumannii. Findings: A. baumannii was isolated from 22 neonates, six of whom were infected. One major PFGE type was identified, assigned to sequence type (ST) 2, corresponding to International Clone II; this was indistinguishable from isolates from the adult ICU in the same hospital. A. baumannii isolates were resistant to aminoglycosides, quinolones and classes of β-lactam antibiotics, but were susceptible to tigecycline and colistin. Carbapenem resistance was associated with the presence of transposon Tn2006 carrying the bla OxA-23 gene. Length of NICU stay, length of exposure to A. baumannii, gestational age, use of invasive devices and length of exposure to invasive devices were significantly associated with acquisition of A. baumannii on univariate analysis, while length of exposure to central venous catheters and assisted ventilation were the only independent risk factors after multi-variate analysis. Conclusions: This XDR A. baumannii outbreak in an NICU was probably caused by intrahospital transfer of bacteria via a colonized neonate whose mother was admitted to the adult ICU. Strengthened infection control measures were necessary to control the outbreak. [ABSTRACT FROM AUTHOR]

The emergence of new synthetic opioids (NSOs) has added complexity to recreational opioid markets worldwide. While NSOs with diverse chemical structures have emerged, brorphine currently remains the only NSO with a piperidine benzimidazolone scaffold. However, the emergence of new generations of NSOs, including brorphine analogues, can be anticipated. This study explored the pharmaco-toxicological, opioid-like effect profile of brorphine alongside its non-brominated analogue (orphine) and three other halogenated analogues (fluorphine, chlorphine, iodorphine). In vitro , radioligand binding assays in rat brain tissue indicated that all analogues bind to the μ-opioid receptor (MOR) with nM affinity. While analogues with smaller-sized substituents showed the highest MOR affinity, further in vitro characterization via two cell-based (HEK 293T) MOR activation (β-arrestin 2 and mini-G αi recruitment) assays indicated that chlorphine, brorphine, and iodorphine were generally the most active MOR agonists. None of the compounds showed significant in vitro biased agonism compared to hydromorphone. In vivo , we investigated the effects of intraperitoneal (IP) administration of the benzimidazolones (0.01–15 mg/kg) on mechanical and thermal antinociception in male CD-1 mice. Chlorphine and brorphine overall induced the highest levels of antinociception. Furthermore, the effects on respiratory changes induced by a fixed dose (15 mg/kg IP) of the compounds were investigated using non-invasive plethysmography. Fluorphine-, chlorphine-, and brorphine-induced respiratory depressant effects were the most pronounced. For some compounds, pretreatment with naloxone (6 mg/kg IP) could not reverse respiratory depression. Taken together, brorphine-like piperidine benzimidazolones are opioid agonists that have the potential to cause substantial harm to users should they emerge as NSOs. This article is part of the Special Issue on "Novel Synthetic Opioids (NSOs)". • Analogues of brorphine have the potential to emerge as new synthetic opioids. • Piperidine benzimidazolones are μ-opioid receptor agonists in vitro. • Chlorphine and brorphine induced the highest levels of antinociception in vivo. • Fluorphine, chlorphine, and brorphine induced pronounced respiratory depression. • Non-opioid-mediated effects may contribute to some of the in vivo effects. [ABSTRACT FROM AUTHOR]

• Dalbavancin is a novel lipoglycopeptide antibiotic with a long half-life, allowing for extended dosing intervals. • Dalbavancin is effective, safe and cost-effective for severe infections by resistant Gram-positive cocci, including ABSSSI. • Dalbavancin resolves critical infections after prior treatment failure, allowing the patient to quickly leave the hospital. • Further studies on off-label use are warranted to define dalbavancin's role in other infections where biofilm is a concern. • Dalbavancin is an effective, well-tolerated treatment for catheter-related BSI due to CoNS and S. aureus , including MRSA. Dalbavancin is a novel lipoglycopeptide antibiotic with a chemical structure similar to teicoplanin. Dalbavancin has been approved and marketed since 2014 in the USA and 2015 in the European Union for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) caused by Gram-positive cocci. ABSSSIs include infectious syndromes such as erysipelas, cellulitis, major cutaneous abscesses that require incision and drainage, and both surgical and traumatic wound infections. In current clinical practice, dalbavancin is also used for cardiac implantable electronic device-related soft tissue infection and other prosthetic infections, and therefore when the presence of biofilm is a concern. In this review, we aimed to highlight our experience with the use of dalbavancin for some of the most hard-to-treat Gram-positive infections, as well as a promising strategy in terms of pharmacoeconomic effectiveness. We describe our current real-life clinical practice with the use of dalbavancin, depicting a few representative clinical cases in order to share our own practice in the hospital setting. [ABSTRACT FROM AUTHOR]

Opioid overdoses, particularly those involving fentanyl-related substances (FRS), present a significant public health challenge in the United States. This structure-activity relationship (SAR) study evaluated the relationship between the chemical structure of seventeen FRS and their in vivo mu-opioid-receptor (MOR) mediated effects. SAR evaluations included fluorine substitutions on the aniline or phenethyl ring and variations in N -acyl chain length. Adult male Swiss Webster mice were administered fluorinated regioisomers of fentanyl, butyrylfentantyl and valerylfentanyl, and compared to MOR standards including morphine, buprenorphine, and fentanyl to determine if they would elicit prototypical opioid-like effects including hyperlocomotion (open-field test), antinociception (warm-water tail-withdrawal test), and hypoventilation (whole-body plethysmography test). To determine if the MOR was the pharmacological mechanism responsible for these effects, naltrexone or naloxone pretreatments were administered to evaluate their actions on FRS-induced antinociception and hypoventilation. There were three main findings. First, FRS elicited hyperlocomotion, antinociception, and hypoventilation in mice to varying degrees, similar to prototypical MOR standards. Second, the rank order of potencies for hypoventilatory effects of FRS were different for each series including FRS with increasing N -acyl chain length (i.e., acetylfentanyl, fentanyl, butyrylfentanyl, valerylfentanyl, hexanoylfentanyl), phenethyl-fluorinated regioisomers (e.g., 2′-fluorofentanyl, 3′-fluorofentanyl, 4′-fluorofentanyl), and aniline-fluorinated regioisomers (e.g., ortho -fluorofentanyl, meta -fluorofentanyl, para -fluorofentanyl). Third, the degree of separation in potencies observed for the antinociceptive and hypoventilatory effects of these drugs did not always follow that which was observed for their antinociceptive and hyperlocomotor effects. This study clarifies the in vivo activities for these FRS and elucidates a SAR for MOR-mediated effects among structural isomers. • Fentanyl-related substances were evaluated for their effects on locomotion, nociception, and ventilation. • Single atom substitutions imparted profound differences in the pharmacokinetic and pharmacodynamic effects of each drug tested. • In general, potency and efficacy decreased with increases in N -acyl chain length. • Ortho -fluorine substitution on the aniline ring typically increased potency. • Antagonist pretreatment attenuated the antinociceptive and hypoventilatory effects of each drug tested except for hexanoylfentanyl. [ABSTRACT FROM AUTHOR]

Background Septic thrombophlebitis increases patient morbidity and mortality following metastatic infections, pulmonary emboli, and/or septic shock. Central venous catheter (CVC) removal for occult septic thrombophlebitis challenges current strategy in neutropenic patients. Patients and methods We prospectively evaluated infection-related mortality in 100 acute leukemia patients, with CVC-related bloodstream infection (CRBSI) after chemotherapy, who systematically underwent ultrasonography to identify the need for catheter removal. Their infection-related mortality was compared with that of a historical cohort of 100 acute leukemia patients, with CRBSI after chemotherapy, managed with a clinically driven strategy. Appropriate antimicrobial therapy was administered in all patients analyzed. Results In the prospective series, 30/100 patients required catheter removal for ultrasonography-detected septic thrombophlebitis after 1 median day from BSI onset; 70/100 patients without septic thrombophlebitis retained their CVC. In the historical cohort, 60/100 patients removed the catheter (persistent fever, 40 patients; persistent BSI, 10 patients; or clinically manifest septic thrombophlebitis, 10 patients) after 8 median days from BSI onset; 40/100 patients retained the CVC because they had not clinical findings of complicated infection. At 30 days median follow-up, one patient died for infection in the ultrasonography-assisted group versus 17 patients in the historical cohort (P < 0.01). With the ultrasonography-driven strategy, early septic thrombophlebitis detection and prompt CVC removal decrease infection-related mortality, whereas clinically driven strategy leads to inappropriate number, reasons, and timeliness of CVC removal. Conclusion Ultrasonography is an easy imaging diagnostic tool enabling effective and safe management of patients with acute leukemia and CRBSI. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring. [Copyright &y& Elsevier]

[Display omitted] • Fentanyl analogs were tested for respiratory depressant effects in freely moving mice. • Each drug elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested. • Benzodioxolefentanyl produced little respiratory depression relative to other drugs tested. • Isobutyrylfentanyl and para -methoxybutyrylfentanyl had unusually favorable safety profiles. • A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs tested. Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para -methoxyfentanyl, para -methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para -methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para -methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED 50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED 50 = 0.96 mg/kg) > 3-furanylfentanyl (ED 50 = 2.60 mg/kg) > crotonylfentanyl (ED 50 = 2.72 mg/kg) > para -methoxyfentanyl (ED 50 = 3.31 mg/kg) > buprenorphine (ED 50 = 10.8 mg/kg) > isobutyrylfentanyl (ED 50 = 13.5 mg/kg) > para -methoxybutyrylfentanyl (ED 50 = 16.1 mg/kg) > thiophenefentanyl (ED 50 = 18.0 mg/kg) > morphine (ED 50 = 55.3 mg/kg) > benzodioxolefentanyl (ED 50 = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR. [ABSTRACT FROM AUTHOR]

Abstract: A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model. [Copyright &y& Elsevier]