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Background: Automated testing instruments (ATIs) are commonly used by clinical microbiology laboratories to perform antimicrobial susceptibility testing (AST), whereas public health laboratories may use established reference methods such as broth microdilution (BMD). We investigated discrepancies in carbapenem minimum inhibitory concentrations (MICs) among Enterobacteriaceae tested by clinical laboratory ATIs and by reference BMD at the CDC. Methods: During 2016–2018, we conducted laboratory- and population-based surveillance for carbapenem-resistant Enterobacteriaceae (CRE) through the CDC Emerging Infections Program (EIP) sites (10 sites by 2018). We defined an incident case as the first isolation of Enterobacter spp (E. cloacae complex or E. aerogenes), Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or K. variicola resistant to doripenem, ertapenem, imipenem, or meropenem from normally sterile sites or urine identified from a resident of the EIP catchment area in a 30-day period. Cases had isolates that were determined to be carbapenem-resistant by clinical laboratory ATI MICs (MicroScan, BD Phoenix, or VITEK 2) or by other methods, using current Clinical and Laboratory Standards Institute (CLSI) criteria. A convenience sample of these isolates was tested by reference BMD at the CDC according to CLSI guidelines. Results: Overall, 1,787 isolates from 112 clinical laboratories were tested by BMD at the CDC. Of these, clinical laboratory ATI MIC results were available for 1,638 (91.7%); 855 (52.2%) from 71 clinical laboratories did not confirm as CRE at the CDC. Nonconfirming isolates were tested on either a MicroScan (235 of 462; 50.9%), BD Phoenix (249 of 411; 60.6%), or VITEK 2 (371 of 765; 48.5%). Lack of confirmation was most common among E. coli (62.2% of E. coli isolates tested) and Enterobacter spp (61.4% of Enterobacter isolates tested) (Fig. 1A), and among isolates testing resistant to ertapenem by the clinical laboratory ATI (52.1%, Fig. 1B). Of the 1,388 isolates resistant to ertapenem in the clinical laboratory, 1,006 (72.5%) were resistant only to ertapenem. Of the 855 nonconfirming isolates, 638 (74.6%) were resistant only to ertapenem based on clinical laboratory ATI MICs. Conclusions: Nonconfirming isolates were widespread across laboratories and ATIs. Lack of confirmation was most common among E. coli and Enterobacter spp. Among nonconfirming isolates, most were resistant only to ertapenem. These findings may suggest that ATIs overcall resistance to ertapenem or that isolate transport and storage conditions affect ertapenem resistance. Further investigation into this lack of confirmation is needed, and CRE case identification in public health surveillance may need to account for this phenomenon.
Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a frequent cause of healthcare-associated infections (HAIs). The CDC Emerging Infections Program (EIP) conducted population and laboratory-based surveillance of CRPA in selected areas in 8 states from August 1, 2016, through July 31, 2018. We aimed to describe the molecular epidemiology and mechanisms of resistance of CRPA isolates collected through this surveillance. Methods: We defined a case as the first isolate of P. aeruginosa resistant to imipenem, meropenem, or doripenem from the lower respiratory tract, urine, wounds, or normally sterile sites identified from a resident of the EIP catchment area in a 30-day period; EIP sites submitted a systematic random sample of isolates to CDC for further characterization. Of 1,021 CRPA clinical isolates submitted, 707 have been sequenced to date using an Illumina MiSeq. Sequenced genomes were classified using the 7-gene multilocus sequence typing (MLST) scheme, and a core genome MLST (cgMLST) scheme was used to determine phylogeny. Antimicrobial resistance genes were identified using publicly available databases, and chromosomal mechanisms of carbapenem resistance were determined using previously validated genetic markers. Results: There were 189 sequence types (STs) among the 707 sequenced genomes (Fig. 1). The most frequently occurring were high-risk clones ST235 (8.5%) and ST298 (4.7%), which were found across all EIP sites. Carbapenemase genes were identified in 5 (<1%) isolates. Overall, 95.6% of the isolates had chromosomal mutations associated with carbapenem resistance: 93.2% had porinD-associated mutations that decrease membrane permeability to the drugs; 24.8% had mutations associated with overexpression of the multidrug efflux pump MexAB-OprM; and 22.9% had mutations associated with overexpression of the endogenous β-lactamase ampC. More than 1 such chromosomal resistance mutation type was present in 37.8% of the isolates. Conclusions: The diversity of the sequence types demonstrates that HAIs caused by CRPA can arise from a variety of strains and that high-risk clones are broadly disseminated across the EIP sites but are a minority of CRPA strains overall. Carbapenem resistance in P. aeruginosa was predominantly driven by chromosomal mutations rather than acquired mechanisms (ie, carbapenemases). The diversity of the CRPA isolates and the lack of carbapenemase genes suggest that this ubiquitous pathogen can readily evolve chromosomal resistance mechanisms, but unlike carbapenemases, these cannot be easily spread through horizontal transfer.
We use the divide-and-conquer and scanning algorithms for calculating Khovanov cohomology directly on the Lee- or Bar-Natan deformations of the Khovanov complex to give an alternative way to compute Rasmussen s-invariants of knots. By disregarding generators away from homological degree 0, we can considerably improve the efficiency of the algorithm. With a slight modification, we can also apply it to a refinement of Lipshitz–Sarkar.
Agomelatine is a new antidepressive drug, that is successfully applied in therapy of insomnia and depression. Until now, there has been no report on its application as add-on medication in therapy for the withdrawl ob benzodiazepine.
We are reporting a case of a forty-year-old male patient who was treated with Agomelatine in lorazepam withdrawl therapy. He showed a considerabel reduction of craving as well as of insomnia and vegetative symptoms.
Therefore there is the question if the substance has its own anti-craving component and to what extent the melatonin-receptor profile is involved.
Implicit memories like consumption habits and conditioned reactions to drug-related stimuli are operational in addiction and relapse. The affective startle paradigm is an attractive tool for the measurement of the incentive salience of drug-related cues. We tested whether the stronger appetitive valence of drug cues, shown in two recent startle studies in smokers, does persist after prolonged abstinence, and may thus contribute to relapse.
We examined the auditory startle reflex magnitude of mildly deprived (4-6 hours) heavy smokers (n = 24), former smokers (n = 16, mean abstinence interval 18 months), and non-smokers (n = 24) while they viewed smoking-related scenes or standardized unpleasant, neutral and pleasant control scenes from the International Affective Picture System.
As expected, non-smokers showed no appetitive reactions toward smoking-cues. In smokers, smoking-cues had both appetitive implicit (startle suppression) and explicit (ratings for valence and craving) motivational effects, resembling those of pleasant scenes and differing from neutral and unpleasant scenes. This effect was more pronounced in smokers who later relapsed after a smoking cessation program, and in smokers consuming less than 20 cigarettes per day. Former smokers, despite reporting no craving and negative reactions to smoking cues, still showed evidence of implicit appetitive valence of these cues.
Nicotine addiction results in automatic appetitive reactions to drug-cues, which does not vanish after prolonged abstinence and which may thus contribute to relapses. Heavy smoking may result in a progressive internalization of smoking habits and a decline in reactivity towards external smoking-associated cues.
Data from large representative epidemiological samples, such as the National Co-morbidity Survey Replication, indicate high co-occurrence of major depressive disorder and alcohol misuse and dependence. Possible mechanisms include common risk factors, affective disorder inducing alcohol use, and alcohol use inducing affective disorder. Overall the findings for a common predisposition are not very strong, but common genetics contributing to the induction of both disorders seem to include the cholinergic muscarinic 2 receptor gene, clock genes and possibly MTHFR. Attempts to group depression and alcoholism into alcohol-induced depression and depression as an independent disorder, or alternatively into externalizing and internalizing alcoholics (characterized by high levels of anxiety and depression), have not gained common acceptance. Data indicate more than one pathway, with differences in subgroups specifically for males and females. A possible mechanism underlying the co-occurrence may be stress vulnerability and alteration of stress vulnerability within the context of major depressive disorder and chronic alcohol use. The interaction seems to be specifically pertinent for an increased risk of relapse. Our understanding of alcohol dependence and major depressive disorder has been based to a considerable degree on animal models. Preclinical co-morbidity studies so far have been rare; one reason being that results vary substantially according to the applied model. Currently the gene/environment interaction and the role of epigenetic processes are increasingly getting into the focus of research, which promises to further our understanding of the mechanism of co-morbidity for alcoholism and major depressive disorder.
It is increasingly recognised that the use of BMI cut-off points for diagnosing obesity (OB) and proxy measures for body fatness in a given population needs to take into account the potential impact of ethnicity on the BMI–fat % relationship in order to avoid adiposity status misclassification. This relationship was studied here in 377 Mauritian schoolchildren (200 boys and 177 girls, aged 7–13 years) belonging to the two main ethnic groups: Indian (South Asian descent) and Creole (African/Malagasy descent), with body composition assessed using an isotopic 2H dilution technique as reference. The results indicate that for the same BMI, Indians have more body fat (and less lean mass) than Creoles among both boys and girls: linear regression analysis revealed significantly higher body fat % by 4–5 units (P < 0·001) in Indians than in Creoles across a wide range of BMI (11·6–34·2 kg/m2) and body fat % (5–52 %). By applying Deurenberg’s Caucasian-based equation to predict body fat % from WHO-defined BMI thresholds for overweight (OW) and OB, and by recalculating the equivalent BMI values using a Mauritian-specific equation, it is shown that the WHO BMI cut-offs for OB and OW would need to be lowered by 4·6–5·9 units in Indian and 2·0–3·7 units in Creole children in the 7–13-year-old age group. These results have major implications for ethnic-based population research towards improving the early diagnosis of excess adiposity in this multi-ethnic population known to be at high risk for later development of type 2 diabetes and CVD.
This chapter examines some of the material aspects of the daily practise of music at court. It investigates the motivations of musical practise at court that took place on a more intimate scale on a daily basis. Schütz notably shows that musical performance at court served purposes of different nature, ranging from entertainment to instruction, from diplomatic tool to image-fashioning, from invitation to the dance to personal recreation. It involved members of the court at every level both as performers and listeners, and was one of the only means by which social barriers could occasionally be blurred. That music was provided by both servants and courtiers is reflected in Shakespeare’s All is True when Queen Katherine requests one of her ladies in waiting to leave her work and perform a song for her in act 3, scene 1. Eventually, Schütz insists on the importance of transmission. Indeed, in order to obtain the skills necessary to discuss music, rulers and courtiers had of course to be instructed in the art. Next to these intimate forms of court performance, then, there existed a pedagogical type of performance: tutors instructing their royal students, both children and adults.