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The incentive structure of a scientist's life is increasingly mimicking economic principles. While intensely criticized, the journal impact factor (JIF) has taken a role as the new currency for scientists. Successful goal-directed behavior in academia thus requires knowledge about the JIF. Using functional neuroimaging we examined how the JIF, as a powerful incentive in academia, has shaped the behavior of scientists and the reward signal in the striatum. We demonstrate that the reward signal in the nucleus accumbens increases with higher JIF during the anticipation of a publication and found a positive correlation with the personal publication record (pJIF) supporting the notion that scientists have incorporated the predominant reward principle of the scientific community in their reward system. The implications of this behavioral adaptation within the ecological niche of the scientist's habitat remain unknown, but may also have effects which were not intended by the community.

Sporadic E (E s) layers are patches of high ionization observed at around 100–140 km height in the E region. Their formation at low latitudes is primarily associated with the diurnal and semidiurnal components of the tidal winds via the ion convergence driven by the wind shear mechanism. However, recent studies have shown the influence of other tidal modes, such as the terdiurnal tide. Therefore, this work investigates the effect of terdiurnal tide-like oscillations on the occurrence and formation of the E s layers observed over Palmas (10.17 ∘ S, 48.33 ∘ W; dip lat. - 7.31 ∘), a low-latitude station in Brazil. The analysis was conducted from December 2008 to November 2009 by using data collected from CADI (Canadian Advanced Digital Ionosonde). Additionally, the E Region Ionospheric Model (MIRE) was used to simulate the terdiurnal tidal component in the E s layer development. The results show modulations of 8 h periods on the occurrence rates of the E s layers during all seasonal periods. In general, we see three well-defined peaks in a superimposed summation of the E s layer types per hour in summer and autumn. We also observed that the amplitude modulation of the terdiurnal tide on the E s occurrence rates minimizes in December in comparison to the other months of the summer season. Other relevant aspects of the observations, with complementary statistical and periodogram analysis, are highlighted and discussed. [ABSTRACT FROM AUTHOR]

Aims: Here, we investigate the impact of phage‐antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug‐resistant (MDR) P. aeruginosa. Methods and Results: After screening 10 well‐characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage‐antibiotic combinations (PAC) against MDR P. aeruginosa, time‐kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage‐meropenem‐colistin and phage‐ciprofloxacin‐colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log10 CFU ml−1) and R10266 (4.50 log10 CFU ml−1) respectively. PAC resulted in regained and improved antibiotic susceptibility to ciprofloxacin (MIC 2 to 0.0625) and meropenem (MIC 32 to 16), respectively, in R9316. Phage resistance was prevented or reduced in the presence of several classes of antibiotics and OMV production was reduced in the presence of phage for both strains, which was associated with significantly improved bacterial eradication. Conclusions: These findings support the potential of phage‐antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS. Significance and Impact of Study: This study identifies novel bactericidal phage‐antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage‐mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing. [ABSTRACT FROM AUTHOR]

Stenotrophomonas maltophilia is an underappreciated source of morbidity and mortality among gram-negative pathogens. Effective treatment options with acceptable toxicity profiles are limited. Phenotypic susceptibility testing via commercial automated test systems is problematic and no Food and Drug Administration breakpoints are approved for any of the first-line treatment options for S maltophilia. The lack of modern pharmacokinetic/pharmacodynamic data for many agents impedes dose optimization, and the lack of robust efficacy and safety data limits their clinical utility. Levofloxacin has demonstrated similar efficacy to trimethoprim-sulfamethoxazole, although rapid development of resistance is a concern. Minocycline demonstrates the highest rate of in vitro susceptibility, however, evidence to support its clinical use are scant. Novel agents such as cefiderocol have exhibited promising activity in preclinical investigations, though additional outcomes data are needed to determine its place in therapy for S maltophilia. Combination therapy is often employed despite the dearth of adequate supporting data. [ABSTRACT FROM AUTHOR]

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance. [ABSTRACT FROM AUTHOR]

Resumen Objetivo La aparición de nueva información sobre las terapias biológicas en la espondiloartritis axial (EspAax) ha impulsado una nueva revisión de las recomendaciones de la Sociedad Española de Reumatología (SER) basadas en la mejor evidencia posible. Estas nuevas recomendaciones pueden servir de referencia para reumatólogos implicados en el tratamiento de estos pacientes. Métodos Se creó un panel formado por nueve reumatólogos expertos en EspAax, previamente seleccionados por la SER mediante una convocatoria abierta. Las fases del trabajo fueron: identificación de las áreas clave para la actualización del consenso anterior, análisis y síntesis de la evidencia científica (sistema modificado de Oxford, CEBM, 2009) y formulación de recomendaciones a partir de esta evidencia y de técnicas de consenso. Resultados Esta revisión de las recomendaciones comporta una actualización en la evaluación de actividad de la enfermedad y objetivos de tratamiento. Incorpora también los nuevos fármacos disponibles, así como sus nuevas indicaciones, y una revisión de los factores predictivos de respuesta terapéutica y progresión del daño radiográfico. Finalmente, estas recomendaciones abordan también las situaciones de fracaso a un primer anti-TNF, así como la posible optimización de la terapia biológica. El documento incluye una tabla de recomendaciones y un algoritmo de tratamiento. Conclusiones Se presenta la actualización de las recomendaciones SER para el uso de terapias biológicas en pacientes con EspAax. Abstract Objective Recent data published on biological therapy in axial spondyloarthritis (axSpA) since the last publication of the recommendations of the Spanish Society of Rheumatology (SER) has led to the generation of a review of these recommendations based on the best possible evidence. These recommendations should be a reference for rheumatologists and those involved in the treatment of patients with axSpA. Methods Recommendations were drawn up following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Centre for Evidence Based Medicine at Oxford. The level of agreement was established through the Delphi technique. Results In this review, we did an update of the evaluation of disease activity and treatment objectives. We included the new drugs with approved therapeutic indication for axSpA. We reviewed both the predictive factors of the therapeutic response and progression of radiographic damage. Finally, we drafted some recommendations for the treatment of patients refractory to anti-tumor necrosis factor, as well as for the possible optimization of biological therapy. The document also includes a table of recommendations and a treatment algorithm. Conclusions We present an update of the SER recommendations for the use of biological therapy in patients with axSpA. [ABSTRACT FROM AUTHOR]

The incentive structure of a scientist’s life is increasingly mimicking economic principles. While intensely criticized, the journal impact factor (JIF) has taken a role as the new currency for scientists. Successful goal-directed behavior in academia thus requires knowledge about the JIF. Using functional neuroimaging we examined how the JIF, as a powerful incentive in academia, has shaped the behavior of scientists and the reward signal in the striatum. We demonstrate that the reward signal in the nucleus accumbens increases with higher JIF during the anticipation of a publication and found a positive correlation with the personal publication record (pJIF) supporting the notion that scientists have incorporated the predominant reward principle of the scientific community in their reward system. The implications of this behavioral adaptation within the ecological niche of the scientist’s habitat remain unknown, but may also have effects which were not intended by the community. [ABSTRACT FROM AUTHOR]

Background CREs are feared pathogens with resistance occurring through the production of carbapenemases. Identification of carbapenemase-producing (CP) organisms assists with proper antimicrobial selection of commonly used agents, such as ceftazidime/avibactam (CA), meropenem/vaborbactam (MV), and tigecycline (TG). AdventHealth Orlando implemented a CRE screening method based on meropenem (MER) and a confirmatory CRE PCR testing in March 2018. Prior to implementing this test, patients were deemed to have CRE infections (CREI) if the organism demonstrated resistance to any carbapenem. The objective of this study was to evaluate the impact of this testing on the utilization of anti-CRE antibiotics. Methods This was a retrospective pre (March 2017–February 2018)- and post (March 2018–February 2019)-implementation study examining the impact of CRE PCR testing. Outcomes included the number of antibiotic days saved, average duration of therapy (DOT), median length of stay (LOS), and change in CP-CRE prevalence. The intervention consisted of the implementation of CRE PCR testing and included inpatients > 18 years old who received either CA, MV, or TG for the treatment of a CREI. Results Post-implementation, 30 unique patients were identified as having a positive K. pneumoniae carbapenemase gene by PCR, indicating a CP-CRE and received CA, MV, or TG; whereas, 42 patients in the pre-implementation group had a CREI and received CA, MV, or TG. Testing to identify CP-CREs led to a 50% reduction in the number of antibiotic days for CA, MV, and TG (575 vs. 287 days, P < 0.0001). Additionally, the average DOT decreased by 2.5 days in the post-implementation group (10.5 days vs. 8 days, P = 0.18) along with a 3.5-day shorter median LOS (15 days vs. 11.5 days, P = 0.48). The CRE prevalence based on resistance only to MER is 0.27%, compared with the previously reported rate of 2.5% that included resistance to ertapenem or MER. Conclusion Implementing CRE PCR testing to identify CP-CRE organisms resulted in a significant reduction in utilization of anti-CRE agents for CREIs. Additionally, the testing algorithm allowed for accurate reporting of our local CRE prevalence. By avoiding CA, MV, or TG in patients without CP-CREs, this has the potential to optimize therapy while reducing collateral damage associated with broad-spectrum agents. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is one of the most common causes of healthcare-associated diseases and is among the top three priority pathogens listed by the World Health Organization (WHO). This Gram-negative pathogen is especially difficult to eradicate because it displays high intrinsic and acquired resistance to many antibiotics. In addition, growing concerns regarding the scarcity of antibiotics against multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa infections necessitate alternative therapies. Bacteriophages, or phages, are viruses that target and infect bacterial cells, and they represent a promising candidate for combatting MDR infections. The aim of this review was to highlight the clinical pharmacology considerations of phage therapy, such as pharmacokinetics, formulation, and dosing, while addressing several challenges associated with phage therapeutics for MDR P. aeruginosa infections. Further studies assessing phage pharmacokinetics and pharmacodynamics will help to guide interested clinicians and phage researchers towards greater success with phage therapy for MDR P. aeruginosa infections. [ABSTRACT FROM AUTHOR]

Background Respiratory infection due to Achromobacter species has been increasingly more common, especially in patients with cystic fibrosis (CF). Recurrent infections in these patients contribute to significant morbidity and mortality as well as lead to repeated antibiotic exposures with subsequent development of multi-drug-resistant (MDR) pathogens. Several recently approved antimicrobials target MDR Gram-negative pathogens, but none are FDA approved for MDR Achromobacter respiratory infections and lack susceptibility breakpoint recommendations. Methods This retrospective analysis evaluated hospitalized patients with MDR Achromobacter respiratory infections from August 2017 to March 2019 at AdventHealth Orlando, a 2,885-bed healthcare system including 8 campuses across Central Florida. The purpose of this descriptive study was to examine novel therapeutic agents for the treatment of respiratory infections due to MDR Achromobacter. Results MDR Achromobacter was isolated in 36 respiratory cultures from 18 unique patients. A. xylosoxidans (61%) and A. denitrificans (22%) were the most frequently isolated species. Mean patient age was 40 years, 56% were female, and 67% had CF. Treatment indications included CF exacerbation (38%), pneumonia (35%), post-lung transplant infection (16%), and other (11%). Twenty-four infections were polymicrobial (67%) and 23 infections included MDR pathogens. Minimum inhibitory concentrations (MIC) of the antibiotics used for treatment were available for 70% of cases. Of the 18 patients with isolated MDR Achromobacter organisms, 72% had MIC changes with 69% exhibiting higher MICs on subsequent testing. Novel agents were used in 63% of cases (Table 1) for an average duration of 10 days. Eravacycline was the most frequently used monotherapy agent (5/6 cases) and the most utilized novel antibiotic (21%). All-cause readmission rates at 30 days was 33%; 92% was due to infection. Inpatient all-cause mortality was 11%. Conclusion Antibiotics available to treat MDR Achromobacter infections are limited and lack standard susceptibility breakpoint recommendations. Based on this evaluation, novel agents, such as eravacycline or meropenem/vaborbactam, may be viable treatment options for patients with MDR Achromobacter respiratory infections. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Rapid and accurate diagnostics are needed to effectively detect and treat primary amoebic meningoencephalitis (PAM) caused by Naegleria fowleri ( Nf ). Delayed diagnosis and similarities to other causes of meningitis contribute to a case mortality rate of >97%. Thus, there is an unmet medical need for a non-invasive liquid biopsy diagnostic method. We sequenced Nf extracellular vesicles (EVs) and identified microRNAs, tRNAs and other small RNAs in Nf -EVs. From these data we selected two prevalent small RNAs as biomarker candidates. We developed an RT-qPCR assay and both small RNAs were detected in Nf -EVs and amoeba-conditioned media. In the mouse model of PAM both small RNA biomarkers were detected in 100% of mouse plasma samples at the end-stage of infection. Notably, smallRNA-1 was detected in the urine of infected mice at timepoints as early as 24h post infection (18/23 mice) and in the plasma as early as 60h post infection (8/8 mice). Additionally, smallRNA-1 was detected in 100% (n=6) of CSF samples from human PAM cases, and in whole blood samples, but not in human plasma from PAM cases. In this study, we discovered small RNAs as biomarkers of Nf infection, one which can be detected reliably in CSF, urine, and whole blood. The RT-qPCR assay is a highly sensitive diagnostic assay that can be conducted in ~3h after receipt of liquid biopsy. The data suggest detection of smallRNA-1 biomarker could provide earlier diagnosis of PAM and be used to monitor biomass of amoebae during treatment., Competing Interests: Competing interests: Authors declare that they have no competing interests.

In the era of antimicrobial resistance, phage-antibiotic combinations offer a promising therapeutic option, yet research on their synergy and antagonism is limited. This study aims to assess these interactions, focusing on protein synthesis inhibitors and cell envelope-active agents against multidrug-resistant bacterial strains. We evaluated synergistic and antagonistic interactions in multidrug-resistant Staphylococcus aureus , Enterococcus faecium , and Pseudomonas aeruginosa strains. Phages were combined with protein synthesis inhibitors [linezolid (LZD), minocycline (MIN), gentamicin (GEN), and azithromycin (AZM)] or cell envelope-active agents [daptomycin (DAP), ceftaroline (CPT), and cefepime (FEP)]. Modified checkerboard minimum inhibitory concentration assays and 24-h time-kill analyses were conducted, alongside one-step growth curves to analyze phage growth kinetics. Statistical comparisons used one-way analysis of variance (ANOVA) and the Tukey test ( P < 0.05). In the checkerboard and 24-h time-kill analyses (TKA) of S. aureus and E. faecium , phage-LZD and phage-MIN combinations were antagonistic (FIC > 4) while phage-DAP and phage-CPT were synergistic (FIC 0.5) (ANOVA range of mean differences 0.52-2.59 log 10 CFU/mL; P < 0.001). For P. aeruginosa , phage-AZM was antagonistic (FIC > 4), phage-GEN was additive (FIC = 1), and phage-FEP was synergistic (ANOVA range of mean differences 1.04-1.95 log 10 CFU/mL; P < 0.001). Phage growth kinetics were altered in the presence of LZD and MIN against S. aureus and in the presence of LZD against a single E. faecium strain (HOU503). Our findings indicate that select protein synthesis inhibitors may induce phage-antibiotic antagonism. However, this antagonism may not solely stem from changes in phage growth kinetics, warranting further investigation into the complex interplay among strains, phage attributes, and antibiotic mechanisms affecting bacterial inhibition.IMPORTANCEIn the face of escalating antimicrobial resistance, combining phages with antibiotics offers a promising avenue for treating infections unresponsive to traditional antibiotics. However, while studies have explored synergistic interactions, less attention has been given to potential antagonism and its impact on phage growth kinetics. This research evaluates the interplay between phages and antibiotics, revealing both synergistic and antagonistic patterns across various bacterial strains and shedding light on the complex dynamics that influence treatment efficacy. Understanding these interactions is crucial for optimizing combination therapies and advancing phage therapy as a viable solution for combating antimicrobial resistance., Competing Interests: The authors declare no conflict of interest.

Pseudomonas aeruginosa -associated infective endocarditis represents difficult-to-treat, deep-seated infections. Phage-antibiotic combinations have shown to eradicate multi-drug resistant (MDR) P. aeruginosa , limit the development of phage resistance, and restore antibiotic sensitivity. The objective of this study was to evaluate the activity of phage-ciprofloxacin (CIP) combinations in 4-day ex vivo simulated endocardial vegetation (SEV) models against drug-resistant P. aeruginosa isolates. Two P. aeruginosa isolates, extensively drug-resistant AR351 and MDR I0003-1, were selected for their drug resistance and sensitivity to phage. Three phages [LL-5504721-AH (LL), E2005-C (EC), and 109] and CIP were evaluated alone and in combination for their activity and influence on drug and phage resistance using 24-h time-kill analysis. The three-phage cocktail (q24h) in combination with CIP (400 mg q12h) was then tested in dynamic 4-day ex vivo SEV models, with reduction of log 10 CFU/mL compared using ANOVA with Bonferroni analysis. Compared to other combinations, CIP-LL-EC-109 demonstrated synergistic and bactericidal activity from starting CFU/g against AR351 and I0003-1 (-Δ5.65 and 6.60 log 10 CFU/g, respectively; P < 0.001). Additionally, CIP-LL-EC-109 mitigated phage resistance, while all other therapies had a high degree of resistance to >1 phages, and all phage-containing regimens prevented CIP mean inhibitory concentration increases compared to CIP alone for both AR351 and I0003-1 at 96 h., Competing Interests: A.E., K.S., A.J.K., D.J.H., R.K., J.A., and S.M.L. have nothing to disclose. M.J.R.: received research support, consulted or participated in a speaker bureau for AbbVie, Basilea, Entasis, La Jolla, Merck, Paratek, Shionogi, T2 Biosystems, and is partially funded by NIAID R21AI163726.

Biofilm-producing Pseudomonas aeruginosa infections pose a severe threat to public health and are responsible for high morbidity and mortality. Phage-antibiotic combinations (PACs) are a promising strategy for combatting multidrug-resistant (MDR), extensively drug-resistant (XDR), and difficult-to-treat P. aeruginosa infections. Ten MDR/XDR P. aeruginosa strains and five P . aeruginosa -specific phages were genetically characterized and evaluated based upon their antibiotic susceptibilities and phage sensitivities. Two selected strains, AR351 (XDR) and I0003-1 (MDR), were treated singly and in combination with either a broad-spectrum or narrow-spectrum phage, phage EM-T3762627-2&#95;AH (EM), or 14207, respectively, and bactericidal antibiotics of five classes in biofilm time-kill analyses. Synergy and/or bactericidal activity was demonstrated with all PACs against one or both drug-resistant P. aeruginosa strains (average reduction: -Δ3.32 log 10 CFU/cm 2 ). Slightly improved ciprofloxacin susceptibility was observed in both strains after exposure to phages (EM and 14207) in combination with ciprofloxacin and colistin. Based on phage cocktail optimization with four phages (EM, 14207, E20050-C (EC), and 109), we identified several effective phage-antibiotic cocktails for further analysis in a 4-day pharmacokinetic/pharmacodynamic in vitro biofilm model. Three-phage cocktail, EM + EC + 109, in combination with ciprofloxacin demonstrated the greatest biofilm reduction against AR351 (-Δ4.70 log 10 CFU/cm 2 from baseline). Of remarkable interest, the addition of phage 109 prevented phage resistance development to EM and EC in the biofilm model. PACs can demonstrate synergy and offer enhanced eradication of biofilm against drug-resistant P. aeruginosa while preventing the emergence of resistance., Competing Interests: M.J.R. received research support, consulted or participated in a speaker bureau for AbbVie, Basilea, Entasis, La Jolla, Merck, Paratek, Shionogi, and T2 Biosystems, and was partially funded by NIAID R21AI163726.

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, laboratory testing, and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.