Registered Replication Report: Rand, Greene, and Nowak (2012).

In an anonymous 4-person economic game, participants contributed more money to a common project (i.e., cooperated) when required to decide quickly than when forced to delay their decision (Rand, Greene & Nowak, 2012), a pattern consistent with the social heuristics hypothesis proposed by Rand and colleagues. The results of studies using time pressure have been mixed, with some replication attempts observing similar patterns (e.g., Rand et al., 2014) and others observing null effects (e.g., Tinghög et al., 2013; Verkoeijen & Bouwmeester, 2014). This Registered Replication Report (RRR) assessed the size and variability of the effect of time pressure on cooperative decisions by combining 21 separate, preregistered replications of the critical conditions from Study 7 of the original article (Rand et al., 2012). The primary planned analysis used data from all participants who were randomly assigned to conditions and who met the protocol inclusion criteria (an intent-to-treat approach that included the 65.9% of participants in the time-pressure condition and 7.5% in the forced-delay condition who did not adhere to the time constraints), and we observed a difference in contributions of -0.37 percentage points compared with an 8.6 percentage point difference calculated from the original data. Analyzing the data as the original article did, including data only for participants who complied with the time constraints, the RRR observed a 10.37 percentage point difference in contributions compared with a 15.31 percentage point difference in the original study. In combination, the results of the intent-to-treat analysis and the compliant-only analysis are consistent with the presence of selection biases and the absence of a causal effect of time pressure on cooperation.

Candida glabrata--unique features and challenges in the clinical management of invasive infections.

Candida glabrata is a pathogenic yeast with several unique biological features. This article provides an up-to-date review on current data and reasoning aspects of this clinically problematic organism. Haploidy, absence of pseudohyphae, facultative anaerobe growth of C. glabrata, as well as its intrinsically low susceptibility to azole antifungals require specific consideration in diagnosis and treatment approaches. As C. glabrata today represents a sizeable percentage of pathogens in candidaemia, the use of azole antifungals in upfront therapy of invasive yeast infections is discouraged by recent guidelines. While the selection of C. glabrata mutants with impaired susceptibility to echinocandins has been described, analyses of several clinical studies indicate an association of improved outcomes with the use of echinocandins as the primary treatment for invasive yeast infections with potential or documented involvement of C. glabrata.

[Liver dysfunctions in intensive care patients--consequences for the treatment of invasive Candida infections]. / Leberfunktionsstörungen in der Intensivmedizin - Konsequenzen für die Therapie invasiver Candidainfektionen.

Liver dysfunction is common among patients on intensive care units (ICU) due to sepsis, chronic liver disease, ischemic hepatitis, drug toxicity and intensive care measures. Critically ill patients with invasive fungal infections should therefore be treated with antifungals that are not metabolized by the liver. This may help to avoid therapeutic complications by drug accumulation, inadequate dosages or drug-drug interactions. Echinocandins are established as the antifungal class of choice in the treatment of invasive Candida infections. Anidulafungin is not hepatically metabolized and may be used without dose adjustments in patients with severe liver dysfunction. It has no known clinically relevant drug interactions. In the primary endpoint of the randomized pivotal trial in patients with candidemia or invasive candidiasis, anidulafungin was statistically superior versus the former standard therapy (fluconazole), with a favourable overall safety profile. More recent study data particularly in ICU patients confirm the efficacy of anidulafungin for these patient groups. Therefore, anidulafungin is an important antifungal treatment option for patients with liver dysfunction.

[Invasive candidiasis in non-neutropenic adults : Guideline-based management in the intensive care unit]. / Invasive Candida-Infektionen bei nichtneutropenischen Erwachsenen : Leitlinienbasiertes Management auf der Intensivstation.

Invasive Candida infections represent a diagnostic and therapeutic challenge for clinicians particularly in the intensive care unit (ICU). Despite substantial advances in antifungal agents and treatment strategies, invasive candidiasis remains associated with a high mortality. Recent guideline recommendations on the management of invasive candidiasis by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) from 2012, the German Speaking Mycological Society and the Paul Ehrlich Society for Chemotherapy (DMykG/PEG) from 2011 and the Infectious Diseases Society of America (IDSA) from 2009 provide valuable guidance for diagnostic procedures and treatment of these infections but need to be interpreted in the light of the individual situation of the patient and the local epidemiology of fungal pathogens. The following recommendations for management of candidemia are common to all three guidelines. Any positive blood culture for Candida indicates disseminated infection or deep organ infection and requires antifungal therapy. Treatment should be initiated as soon as possible. Removal or changing of central venous catheters or other foreign material in the bloodstream is recommended whenever possible. Ophthalmological examination for exclusion of endophthalmitis and follow-up blood cultures during therapy are also recommended. Duration of therapy should be 14 days after clearance of blood cultures and resolution of symptoms. Consideration of surgical options and a prolonged antifungal treatment (weeks to months) are required when there is organ involvement. During the last decade several new antifungal agents were introduced into clinical practice. These innovative drugs showed convincing efficacy and favorable safety in randomized clinical trials. Consequently, they were integrated in recent therapeutic guidelines, often replacing former standard drugs as first-line options. Echinocandins have emerged as the generally preferred primary treatment in candidemia. The expert panel of ESCMID views fluconazole only as a marginally recommended therapy for this indication. The use of amphotericin B deoxycholate should be generally avoided because of toxicity.

Practical considerations on current guidelines for the management of non-neutropenic adult patients with candidaemia.

Recent guideline recommendations on the management of candidaemia provide valuable treatment guidance for routine clinical practice, but need to be interpreted in the light of the actual situation of the patient and the local epidemiology of fungal infections. Echinocandins emerge as the generally preferred primary treatment. Treatment should be initiated immediately after notification of a Candida-positive blood culture in all patients. Ambiguous issues include the definition of optimum duration of treatment, the indication and time point to step down to oral azoles, catheter management, and the appropriate approach in critically ill patients at high risk for candidaemia in the absence of definitive proof of infection. Patients with clinical suspicion of antifungal treatment failure need prompt workup for adequacy of treatment, focal sources of sustained infection and potential superinfection.

Recurrent candidaemia and pacemaker wire infection with Candida albicans.

Recurrent candidaemia is both a cause and a symptom of deep organ candidiasis or infection of foreign bodies (e.g. central venous line, other indwelling catheter or pacemaker wire) and is associated with significant morbidity and mortality. This case report demonstrates that in the event of pacemaker wire infection with Candida and when it is not possible to remove the infected pacemaker wire, treatment with an echinocandin, such as anidulafungin, can be safe and successful.

[Innovative antifungals for treatment of invasive fungal infections]. / Innovative Antimykotika zur Therapie invasiver Pilzinfektionen.

Invasive fungal infections have gained importance in many areas of clinical medicine and represent a growing diagnostic and therapeutic challenge for clinicians. During the last decade, several new antifungals were introduced into routine therapy: two second-generation triazoles and the new class of echinocandins. These innovative drugs showed convincing efficacy and favorable safety in randomized clinical trials. Consequently, they were integrated in recent therapeutic guidelines, often replacing former standard drugs as first-line options. The echinocandins (anidulafungin, caspofungin, micafungin) primarily have gained a central role in the treatment of invasive Candida infections, while the novel triazoles voriconazole and posaconazole established themselves as the current mainstays in therapy and prophylaxis of invasive fungal infections, particularly aspergillosis, in hemato-oncologic high-risk patients.

Current aspects of invasive candidiasis and aspergillosis in adult intensive care patients.

Sepsis is a leading cause of death in the intensive care unit (ICU), with Candida spp. in the forefront among the important pathogens. As recent studies have shown, survival outcome is strongly influenced by adequate antifungal therapy at an early stage that is often delayed by the time lag associated with microbiological diagnosis. Risk factor-based prediction models have a high negative predictive value, but positive prediction of candidaemia in the individual patient remains elusive. New antigen- or DNA-based methods for early diagnosis still await clinical validation. Their routine use is hampered by methodological issues. Species distribution of invasive Candida isolates in the ICU appears to be influenced primarily by age, previous hospitalisation and colonising species. In the context of the importance of adequate first-line treatment, recent guidelines favour the use of echinocandins in critically ill patients with symptoms evoking high suspicion of invasive candidiasis. This is supported by robust clinical trial data, a few interactions and low toxicity. Fluconazole is characterised by reduced activity against some important Candida species, elevated rates of persistent infection seen in comparative trials. Amphotericin B deoxycholate should be considered obsolete in ICU patients because of its high toxicity. Invasive aspergillosis (IA) is a rare devastating infection in the general ICU population, but some centres have reported elevated incidences and underdiagnosis as determined in autopsy-controlled studies. Treatment with mould-active agents such as voriconazole must be initiated early in patients with suspected IA.

[Therapy of candidemia and invasive candidiasis according to guidelines]. / Leitliniengerechte Therapie: Candidämie/invasive Candidiasis.

Invasive fungal infections on the intensive care unit are predominantly caused by Candida spp., most frequently manifesting as candidemia. In spite of increasing treatment options during the last two decades, mortality of invasive candidiasis remains high with 20 to 50%. With the echinocandins, a new class of antifungal drugs with activity against clinically relevant Aspergillus and Candida spp. has become available since the beginning of the new millennium. The echinocandins have shown convincing efficacy in numerous multicentre, mostly double-blinded clinical trials. These trials compared current standard treatment regimens with the echinocandins anidulafungin, caspofungin, and micafungin. All trials observed non-inferiority of the new drugs against the standard treatment; in the case of anidulafungin, superiority against fluconazole was demonstrated. These results of the trials had resulted in modification of the current guidelines for the treatment of candidemia and invasive candidiasis. Especially in ICU patients frequently showing single- or multi-organ failure and receiving a multitude of drugs with complex interactions, echinocandins have become the treatment of first choice for candidemia.

[Invasive candidosis in intensive care unit patients]. / Systemische Candida-Infektionen bei Intensivpatienten.

The incidence of invasive candidosis is increasing worldwide and the mortality is high. In the intensive care unit diagnostic measurements, correct evaluation of the findings and the right indication for antifungal treatment remain problematic. So determination of potential risk factors is very important. The therapeutic use of antifungal drugs is often limited by important disadvantages like inadequate spectrum, application form or side effects. New antifungals give hope for the near future.

The effects of routine strength on adaptation and information search in recurrent decision making.

The strength of decision routines was manipulated within a computer-controlled micro world simulation involving recurrent decision making. During a learning phase, participants were led to prefer a certain brand of an industrial good either about 15 times in a weak routine or about 30 times in a strong routine condition. In the test phase of Experiment 1, participants were confronted with changes in the microworld that rendered the routine obsolete. Routine maintenance over a series of repeated acquisition decisions was assessed as the major dependent variable. Although new information clearly suggested that a deviation from the routine would be beneficial, strong routine participants were more likely to maintain the routine compared to weak routine participants and a control group in which a comparable option (same outcome probabilities as the routine) carried an unfamiliar brand label. Experiment 2 investigated the effects of routine strength on information search. After having learned the routine, participants were asked to make one final decision involving the routine. The task was either framed as being similar to the learning task or as being novel. Before making the final decision, participants were asked to consider new information about the alternatives. Strong routine participants in the familiar task condition preferred information that favored the routine and avoided unfavorable information. If the task was framed as being novel, such confirmation biases disappeared completely. In contrast, weak routine participants exhibited a moderate confirmation bias in their searches independent from task framing.

Sequence analysis of an internal 9.72-kb segment from the 30-kb denitrification gene cluster of Pseudomonas stutzeri.

The DNA segment was sequenced that links the nir-nor and nos gene clusters for denitrification of Pseudomonas stutzeri ATCC 14405. Of 10 predicted gene products, four are putative membrane proteins. Sequence similarity was detected with the subunit III of cytochrome-c oxidase (ORF175), PQQ3 of the biosynthetic pathway for pyrrolo-quinoline quinone (ORF393), S-adenosylmethionine-dependent uroporphyrinogen-III C-methyltransferase (ORF278), the cytochrome cd1 nitrite reductase and the NirF protein involved in the biosynthesis of heme d1 (ORF507), LysR type transcriptional regulators (ORF286), short-chain alcohol dehydrogenases (ORF247), and a hypothetical protein, YBEC, of Escherichia coli (ORF57). The current data together with previous work establish a contiguous DNA sequence of 29.2 kb comprising the supercluster of nos-nir-nor genes for denitrification in this bacterium.

Copper-containing nitrite reductase from Pseudomonas aureofaciens is functional in a mutationally cytochrome cd1-free background (NirS-) of Pseudomonas stutzeri.

The structural gene, nirK, for the respiratory Cu-containing nitrite reductase from denitrifying Pseudomonas aureofaciens was isolated and sequenced. It encodes a polypeptide of 363 amino acids including a signal peptide of 24 amino acids for protein export. The sequence showed 63.8% positional identity with the amino acid sequence of "Achromobacter cycloclastes" nitrite reductase. Ligands for the blue, type I Cu-binding site and for a putative type-II site were identified. The nirK gene was transferred to the mutant MK202 of P. stutzeri which lacks cytochrome cd1 nitrite reductase due to a transposon Tn5 insertion in its structural gene, nirS. The heterologous enzyme was active in vitro and in vivo in this background and restored the mutationally interrupted denitrification pathway. Transfer of nirK to Escherichia coli resulted in an active nitrite reductase in vitro. Expression of the nirS gene from P. stutzeri in P. aureofaciens and E. coli led to nonfunctional gene products. Nitrite reductase activity of cell extract from either bacterium could be reconstituted by addition of heme d1, indicating that both heterologous hosts synthesized a cytochrome cd1 without the d1-group.