Doripenem in hospital infections: a focus on nosocomial pneumonia, complicated intra-abdominal infections, and complicated urinary tract infections

Doripenem is the latest carbapenem on the market to date. Although not an antibiotic in a new class, it offers a glimmer of hope in combating serious infections secondary to multidrug-resistant Gram-negative bacteria when we have not seen a new class of antibacterial, particularly for Gram-negative bacteria, for more than 10 years. In vitro, doripenem exhibits a broad spectrum of activity against Gram-positive and Gram-negative bacteria, including extended-spectrum β-lactamase (ESBL) and Amp-C β-lactamase producing Enterobacteriaceae and anaerobes. Doripenem also exhibits better in vitro activity against Pseudomonas aeruginosa compared to other anti-pseudomonal carbapenems. It combines the desirable activities of both imipenem and meropenem. It has similar activity to imipenem against Gram-positive pathogens and has the antimicrobial spectrum of meropenem against Gram-negative organisms. Several randomized clinical trials have demonstrated that doripenem is non-inferior to meropenem, imipenem, piperacillin/tazobactam, or levofloxacin in its efficacy and safety profile in treating a wide range of serious bacterial infections including intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia. Due to its wide spectrum of activity and good safety profile it is susceptible to misuse leading to increasing rates of resistance. Judicious use should be considered when using doripenem as a first-line agent or drug of choice for serious infections. Doripenem is a well-tolerated drug with common adverse effects including headache, nausea and diarrhea. Caution should be used in patients with hypersensitivity to carbapenems and adverse reactions to β-lactam agents. Dosage adjustment is needed for patients with renal impairment. Doripenem has demonstrated economic and clinical benefits. It has been shown to reduce hospital length of stay and duration of mechanical ventilation for intensive care unit (ICU) patients. Therefore, doripenem is a welcome addition to our limited armamentarium of antibiotics available to treat serious bacterial infections in hospitalized patients

Attachment-specific speech patterns induce dysphoric mood changes in the listener as a function of individual differences in attachment characteristics and psychopathology

Objectives Early childhood experiences influence cognitive-emotional development, with insecure attachment predisposing to potential psychopathologies. We investigated whether narratives containing attachment-specific speech patterns shape listeners’ emotional responses and social intentions. Design First, 149 healthy participants listened to three narratives characteristic for secure, insecure-preoccupied, and insecure-dismissing attachment. Following each narrative, the wellbeing and interpersonal reactivity as a particular aspect of emotional reactivity of the listener were assessed. Likewise, psychopathological aspects of personality were evaluated. A follow-up study compared 10 psychosomatic patients with a current depressive episode and/or personality disorder with distinct depressive symptoms and 10 age- and gender-matched healthy controls. Methods Effects of narratives on listeners’ mental state were tested with repeated-measures AN(C)OVA. Mediating effects in the listener (attachment characteristics in the context of personality traits) were explored. Narrative effects were compared between patients and controls. Results Listening to insecure attachment narratives reduced wellbeing in controls. Nevertheless, tendency for social interaction was highest following the insecure-preoccupied narrative. Importantly, listeners’ individual attachment characteristics mediated the relationship between wellbeing/interpersonal reactivity following the insecure-preoccupied narrative and levels of psychopathology. Furthermore, compared with healthy participants, patients showed higher emotional reactivity following exposure to the insecure-preoccupied narrative, represented by lower wellbeing and lower estimation of friendliness towards the narrator. Conclusions Exposure to attachment-specific speech patterns can result in dysphoric mood changes. Specifically, the insecure-preoccupied narrative influenced the listeners’ emotional state, which was further mediated by the individual attachment patterns and psychopathological personality characteristics. This deepens the understanding of interpersonal processes, especially in psychotherapeutic settings

On Measuring Non-Recursive Trade-Offs

We investigate the phenomenon of non-recursive trade-offs between descriptional systems in an abstract fashion. We aim at categorizing non-recursive trade-offs by bounds on their growth rate, and show how to deduce such bounds in general. We also identify criteria which, in the spirit of abstract language theory, allow us to deduce non-recursive tradeoffs from effective closure properties of language families on the one hand, and differences in the decidability status of basic decision problems on the other. We develop a qualitative classification of non-recursive trade-offs in order to obtain a better understanding of this very fundamental behaviour of descriptional systems

Zeros of the i.i.d. Gaussian power series: a conformally invariant determinantal process

Consider the zero set of the random power series f(z)=sum a_n z^n with i.i.d. complex Gaussian coefficients a_n. We show that these zeros form a determinantal process: more precisely, their joint intensity can be written as a minor of the Bergman kernel. We show that the number of zeros of f in a disk of radius r about the origin has the same distribution as the sum of independent {0,1}-valued random variables X_k, where P(X_k=1)=r^{2k}. Moreover, the set of absolute values of the zeros of f has the same distribution as the set {U_k^{1/2k}} where the U_k are i.i.d. random variables uniform in [0,1]. The repulsion between zeros can be studied via a dynamic version where the coefficients perform Brownian motion; we show that this dynamics is conformally invariant.Comment: 37 pages, 2 figures, updated proof

Investigation of the association of Apgar score with maternal socio-economic and biological factors: an analysis of German perinatal statistics

PURPOSE: To examine the relationship of 5-min Apgar score with maternal socio-economic and biological factors. METHODS: We analyzed data from 465,964 singleton pregnancies (37–41 weeks’ gestation) from the German perinatal statistics of 1998–2000. Using a logistic regression model we analyzed the incidence of low (0–6) 5-min Apgar scores in relation to these maternal factors: body mass index (BMI), age, previous live births, country of origin, occupation, single mother status, working during pregnancy, and smoking. RESULTS: A low Apgar score was more common in overweight [adjusted odds ratio (OR) 1.24; 95% confidence interval (CI) 1.10–1.40; P < 0.001] and obese [OR 1.92 (95% CI 1.67–2.20); P < 0.001] compared to normal weight women. A low Apgar score was also more common for women aged >35 years compared to those aged 20–35 years [OR 1.35 (95% CI 1.16–1.58); P < 0.001]. Furthermore, odds of a low Apgar score were higher for women with no previous live births compared to those with one or more previous live births [OR 1.52 (95% CI 1.37–1.70); P < 0.001]. Socio-economic factors did not convincingly influence Apgar scores. CONCLUSIONS: There was an influence of the biological maternal factors age, BMI, and parity on the 5-min Apgar score. There was no convincing effect of socio-economic factors on Apgar score in our study population. Possible reasons for this are discussed

Weinberg like sum rules revisited

The generalized Weinberg sum rules containing the difference of isovector vector and axial-vector spectral functions saturated by both finite and infinite number of narrow resonances are considered. We summarize the status of these sum rules and analyze their overall agreement with phenomenological Lagrangians, low-energy relations, parity doubling, hadron string models, and experimental data.Comment: 31 pages, noticed misprints are corrected, references are added, and other minor corrections are mad

Inducing circular RNA formation using the CRISPR endoribonuclease Csy4

Circular RNAs (circRNAs) are highly stable, covalently closed RNAs that are regulated in a spatiotemporal manner and whose functions are largely unknown. These molecules have the potential to be incorporated into engineered systems with broad technological implications. Here we describe a switch for inducing back-splicing of an engineered circRNA that relies on the CRISPR endoribonuclease, Csy4, as an activator of circularization. The endoribonuclease activity and 3' end-stabilizing properties of Csy4 are particularly suited for this task. Coexpression of Csy4 and the circRNA switch allows for the removal of downstream competitive splice sites and stabilization of the 5' cleavage product. This subsequently results in back-splicing of the 5' cleavage product into a circRNA that can translate a reporter protein from an internal ribosomal entry site (IRES). Our platform outlines a straightforward approach toward regulating splicing and could find potential applications in synthetic biology as well as in studying the properties of different circRNAs

Somatic Accumulation of GluA1-AMPA Receptors Leads to Selective Cognitive Impairments in Mice

© 2018 Bannerman, Borchardt, Jensen, Rozov, Haj-Yasein, Burnashev, Zamanillo, Bus, Grube, Adelmann, Rawlins and Sprengel. The GluA1 subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice (Gria1R/R), expressing the “trafficking compromised” GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice. These immunohistological changes were accompanied by a strong reduction of somatic AMPAR currents in CA1, and a reduction of plasticity (short-term and long-term potentiation, STP and LTP, respectively) in the CA1 subfield following tetanic and theta-burst stimulation. Nevertheless, spatial reference memory acquisition in the Morris water-maze and on an appetitive Y-maze task was unaffected in Gria1R/R mice. In contrast, spatial working/short-term memory during both spontaneous and rewarded alternation tasks was dramatically impaired. These findings identify the GluA1(Q600R) mutation as a loss of function mutation that provides independent evidence for the selective role of GluA1 in the expression of short-term memory

Nonpathological Extracellular Amyloid Is Present during Normal Epididymal Sperm Maturation

Amyloids are aggregated proteins characterized by a specific cross-β-sheet structure and are typically associated with neurodegenerative diseases including Alzheimer's disease. Recently, however, several nonpathological amyloids have been found in intracellular organelles of normal mammalian tissues suggesting that amyloid may also carry out biological functions. We previously have shown that the epididymal cystatin CRES (cystatin-related epididymal spermatogenic), cst8, a reproductive-specific member of the cystatin superfamily of cysteine protease inhibitors, forms amyloid in vitro suggesting that CRES amyloid may also form in vivo within the epididymal lumen. Here we show that amyloid structures containing CRES are a component of the normal mouse epididymal lumen without any apparent cytotoxic effects on spermatozoa and that these structures change along the length of the tubule. These studies suggest the presence of a functional amyloid structure that may carry out roles in sperm maturation or maintenance of the luminal milieu and which itself may undergo maturational changes along the epididymis. In contrast to previous examples of functional amyloid which were intracellular, our studies now show that nonpathological/functional amyloid can also be extracellular. The presence of an extracellular and nonpathological amyloid in the epididymis suggests that similar amyloid structures may be present in other organ systems and may carry out distinctive tissue-specific functions